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Biomedical subjects

M Manohar

Publications and source records attributed to M Manohar.

At least 55 records · Page 3Linked to original sources

Differential regulation of antioxidant enzymes in response to oxidants.

We have demonstrated the selective induction of manganese superoxide dismutase (MnSOD) or catalase mRNA after exposure of tracheobronchial epithelial cells in vitro to different oxidant stresses. Addition of H2O2 caused a dose-dependent increase in catalase mRNA in both exponentially growing and confluent cells. A 3-fold induction of catalase mRNA was seen at a nontoxic dose of 250 microM H2O2. Increase in the steady-state mRNA levels of glutathione peroxidase (GPX) and MnSOD were less striking. Expression of catalase, MnSOD, and GPX mRNA was highest in confluent cells. In contrast, constitutive expression of copper and zinc SOD (CuZnSOD) mRNA was greatest in dividing cells and was unaffected by H2O2 in both exponentially growing and confluent cells. MnSOD mRNA was selectively induced in confluent epithelial cells exposed to the reactive oxygen species-generating system, xanthine/xanthine oxidase, while steady-state levels of GPX, catalase, and CuZnSOD mRNA remained unchanged. The 3-fold induction of MnSOD mRNA was dose-dependent, reaching a peak at 0.2 unit/ml xanthine oxidase. MnSOD mRNA increases were seen as early as 2 h and reached maximal induction at 24 h. Immunoreactive MnSOD protein was produced in a corresponding dose- and time-dependent manner. Induction of MnSOD gene expression was prevented by addition of actinomycin D and cycloheximide. These data indicate that epithelial cells of the respiratory tract respond to different oxidant insults by selective induction of certain antioxidant enzymes. Hence, gene expression of antioxidant enzymes does not appear to be coordinately regulated in these cell types.

Animals↗

Diaphragmatic energetics during prolonged exhaustive exercise.

The present study was carried out to examine diaphragmatic O2 extraction and lactate and ammonia production during prolonged exhaustive exercise. Experiments were performed on nine healthy exercise-conditioned ponies in which catheters had been implanted in the phrenic vein previously. Blood-gas variables and lactate and ammonia concentrations were determined on simultaneously obtained arterial and phrenic-venous blood samples at rest and during 30 min of exertion at 15 mph + 7% grade (heart rate, 200 beats/min; approximately 90% of maximum). Arterial O2 tension and saturation were maintained near resting value but CO2 tension decreased markedly with exercise, and because of increased hemoglobin concentration, arterial O2 content rose. Concomitantly, phrenic venous O2 tension, saturation and content decreased markedly (23.6 +/- 1 mm Hg, 24.5 +/- 2%, 5.2 +/- 0.3 ml/dl at 3 min of exertion) and significant fluctuations did not occur as exercise duration progressed to 30 min. Diaphragmatic arteriovenous O2 content difference and O2 extraction rose from 4 +/- 0.3 to 16 +/- 0.5 ml/dl and from 30 +/- 3 to 75 +/- 1% at 3 min of exercise, and significant deviations did not occur as exercise duration progressed. Arterial lactate and ammonia levels increased during exercise, indicating their release from working limb muscles. Phrenic-venous values of lactate and ammonia did not exceed arterial values. Ponies sweated profusely and were unable to keep up with the belt speed in the last 4 to 5 min of exercise. Constancy of phrenic arteriovenous O2 content difference in exercise indicated ability to adjust perfusion in diaphragm so as to adequately meet its O2 needs.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerobiosis↗

Studies on cytosolic superoxide dismutase from intestinal mucosa.

CuZn superoxide dismutase from monkey (Macaca radiata) intestinal mucosa was purified to homogenity. The enzyme showed a subunit molecular weight of 16000. The enzyme preparation from intestinal mucosa of rat, rabbit, guinea-pig and monkey was distinctly different in electrophoretic mobility and in elution profile on ion-exchange chromatography, possibly due to their difference in charge. The difference may not be due to glycosylation, since the enzyme was not stained for glycoprotein. Polyclonal antibody against purified monkey enzyme inhibited the activity of intestinal CuZn superoxide dismutase from rat, rabbit and guinea-pig. Thus it appears that intestinal CuZn superoxide dismutases from different sources, despite being similar in immunological and other properties, differ in certain amino acids and hence in charge.

Animals↗

Diaphragm does not produce ammonia or lactate during high-intensity short-term exercise.

To ascertain whether costal diaphragm engages in ammonia and lactate production (like limb muscles) during high-intensity short-term exercise, experiments were carried out on six healthy trained ponies in which phrenic venous catheters had been implanted 5-9 days earlier. Simultaneous anaerobically obtained blood samples from abdominal aorta and the phrenic vein at rest and during 4 min of exertion at 32 km/h and at a 7% grade were analyzed for blood-gas variables as well as lactate and ammonia concentrations using standard procedures. At rest, heart rate was 47 +/- 4 beats/min and the diaphragmatic O2 extraction was 26.5%. With exercise, heart rate rose to 218 +/- 6 beats/min, marked acidosis and hyperventilation occurred, and the diaphragmatic O2 extraction increased threefold (80.9%). Such exercise is known to dramatically increase the work of breathing as respiratory frequency and change in pleural pressure approach 138 +/- 4 breaths/min and 30 +/- 3 cmH2O, respectively. Despite the fact that phrenic-venous O2 tension of exercised ponies decreased to 15.5 +/- 0.6 Torr, the phrenic-venous lactate and ammonia concentrations did not exceed corresponding arterial values. These data thus revealed that the diaphragm is uniquely unlike limb muscles, which at high workloads readily engage in net ammonia and lactate production, and that the diaphragmatic energy needs during high-intensity short-term exercise are primarily met by aerobic metabolism.

Ammonia↗

Inspiratory and expiratory muscle perfusion in maximally exercised ponies.

The present study was carried out on seven healthy ponies to examine the extent of blood flow in various inspiratory and expiratory muscles at rest and during maximal exertion as well as to determine the proportion of cardiac output needed to perfuse respiratory muscles during these conditions. Tissue blood flow was studied with 15 micron-diameter radionuclide-labeled microspheres injected into the left ventricle during steady conditions. The inspiratory and expiratory muscles comprised 2.41 and 3.05% of body weight, respectively, and received 6.17 and 3.75% of the cardiac output at rest. With maximal exercise, heart rate (from 55 +/- 3 to 218 +/- 4 beats/min), mean aortic pressure (from 125 +/- 5 to 170 +/- 6 mmHg), and cardiac output (from 96 +/- 11 to 730 +/- 78 ml.min-1.kg-1) increased markedly. During exercise blood flow increased significantly in all respiratory muscles (P less than 0.0001) as vascular resistance decreased precipitously. Marked heterogeneity of perfusion existed among various inspiratory as well as expiratory muscles during exercise. Among the inspiratory muscles, the highest perfusion occurred in the diaphragm followed by serratus ventralis, and among the expiratory muscles, the highest perfusion occurred in the internal oblique abdominis and the transverse thoracis (triangularis sterni). Collectively, the inspiratory (8.44%) and expiratory (6.35%) muscle blood flow comprised 14.8 +/- 1.2% of the cardiac output during maximal exercise, a significant increase above resting value, whereas renal fraction of cardiac output decreased from 21% (at rest) to 0.72%.

Animals↗

Diaphragmatic perfusion heterogeneity during exercise with inspiratory resistive breathing.

Regional distribution of diaphragmatic blood flow (Q; 15-microns-diam radionuclide-labeled microspheres) was studied in normal (n = 7) and laryngeal hemiplegic (LH; n = 7) ponies to determine whether the added stress of inspiratory resistive breathing during maximal exercise may cause 1) redistribution of diaphragmatic Q and 2) crural diaphragmatic Q to exceed that in maximally exercising normal ponies. LH-induced augmentation of already high exertional work of breathing resulted in diminished locomotor exercise capacity so that maximal exercise in LH ponies occurred at 25 km/h compared with 32 km/h for normal ponies. The costal and crural regions received similar Q in both groups at rest. However, exercise-induced increments in perfusion were significantly greater in the costal region of the diaphragm. At 25 km/h, costal diaphragmatic perfusion was 154 and 143% of the crural diaphragmatic Q in normal and LH ponies. At 32 km/h, Q in costal diaphragm of normal ponies was 136% of that in the crural region. Costal and crural diaphragmatic Q in LH ponies exercised at 25 km/h exceeded that for normal ponies but was similar to the latter during exercise at 32 km/h. Perfusion pressure for the three conditions was also similar. It is concluded that diaphragmatic perfusion heterogeneity in exercising ponies was preserved during the added stress of inspiratory resistive breathing. It was also demonstrated that vascular resistance in the crural and costal regions of the diaphragm in maximally exercised LH ponies remained similar to that in maximally exercising normal ponies.

Airway Resistance↗

Tracheobronchial perfusion during exercise in ponies.

Tracheobronchial circulation during exercise has previously not been examined. Therefore blood flow to the trachea and bronchi (up to 7th generation of branching) was studied in seven healthy adult ponies at rest and during the 3rd and 10th min of exercise performed at a treadmill speed setting of 25 km/h. The ambient air temperature varied from 19 to 20 degrees C and humidity from 35 to 45%. To determine blood flow radionuclide-labeled 15-microns-diameter microspheres were injected into the left ventricle via a catheter advanced from the left carotid artery (exposed using local anesthesia), and a reference sample was obtained from the aorta. Adequate mixing of microspheres with blood was demonstrated by similar perfusion values for left and right kidneys. Exercise increased heart rate (194 +/- 9 and 200 +/- 7 beats/min) and mean aortic pressure (169 +/- 8 and 156 +/- 4 mmHg) of ponies at 3rd and 10th min. Tracheal blood flow (6.7 +/- 0.5 ml.min-1 x 100 g-1) of resting ponies was only one-third of the bronchial blood flow (21.6 +/- 4.9 ml.min-1 x 100 g-1) Significant changes in tracheal perfusion did not occur at 3rd or 10th min of exercise. Although bronchial perfusion also did not change at the 3rd min of exercise, it rose dramatically to 202.8 +/- 30.3 ml.min-1 x 100 g-1 during the 10th min. Concomitantly, renal blood flow decreased at 10th min of exertion. The large increase in bronchial blood flow at 10th min of exertion may have been necessitated by the need to help dissipate body heat.

Animals↗

Isoproterenol-induced maximal heart rate in normothermic and hyperthermic horses.

The heart rate (HR) induced by maximal beta-adrenergic activation, which was elicited by infusion of isoproterenol, was studied in 8 healthy horses before (control) and after hyperthermia was induced by IV administration of 2,4-dinitrophenol (DNP). Isoproterenol was administered IV at 1.0 micrograms.kg-1.min-1 for 3 minutes, and the HR was determined during the final 30 seconds of the infusion. As the rectal temperature increased (P less than 0.001) from 38.2 +/- 0.1 C (mean +/- SEM; normothermic control) to 40.1 +/- 0.1 C at 60 minutes after DNP administration, the isoproterenol-induced HR also increased from 198 +/- 4 beats/min (control) to 214 +/- 4 beats/min (P less than 0.001). It appeared that the values of HR achieved with maximal beta-adrenergic activation were augmented by the hypermetabolic, hyperthermic state induced by DNP.

2,4-Dinitrophenol↗

Effect of age on isoproterenol-induced maximal heart rate in horses.

The effect of age on maximal heart rate induced by IV infusion of isoproterenol was studied in 19 healthy, sedentary, normothermic horses ranging in age from 0.25 to 9.90 years. Isoproterenol was administered IV (1.0 micrograms/kg of body weight/min) for 3 minutes, and the heart rate attained during the last 30 seconds of the infusion was determined. Linear regression of the maximal heart rate on age suggested that the rate decreased with age in a trend described by the equation: maximal heart rate (beats/min) = 209.63 - 3.28 x age (years). The regression coefficient (r) for this relation was 0.769 (P less than 0.001). These data indicate that as healthy horses age, their beta-adrenoceptor-mediated maximal chronotropic response is diminished.

Age Factors↗

A study of the effect of isoflurane anaesthesia on equine skeletal muscle perfusion.

The effects of 1.1, 1.5 and 1.8 MAC (minimum alveolar concentration) isoflurane-02 anaesthesia on skeletal muscle blood flow, 02 delivery and vascular resistance were studied in the non-dependent region of seven healthy normothermic, isocapnoeic ponies. Muscle blood flow was determined with 15 microns diameter radionuclide labelled microspheres that were injected into the left ventricle. Muscle blood flow during anaesthesia was compared to unanaesthetised (control) measurements. Isoflurane administration caused a dose dependent decrease in mean aortic pressure, and skeletal muscle (temporalis, triceps brachii, longissimus dorsi, gluteus medius, biceps femoris, vastus lateralis) blood flow. However, in the masseter, triceps brachii at 1.1 and 1.5 MAC, and longissimus dorsi lumborum at 1.1 MAC anaesthesia, blood flow values were not different from the control value. Vascular resistance did not change significantly in any of the muscles with any concentration of isoflurane. With the exception of the masseter muscle, isoflurane anaesthesia also decreased skeletal muscle 02 delivery. There were no significant differences in the muscle parameters studied between the three concentrations of isoflurane. Because skeletal muscle vascular resistance was unchanged throughout the study, it is possible that there may be an interference of 'autoregulation' in the skeletal muscle vascular beds of isocapnoeic ponies during isoflurane-02 anaesthesia.

Anesthetics, Inhalation↗

Purification and chemical characterisation of the inhibitor of lipid peroxidation from intestinal mucosa.

The antioxidant previously isolated from intestinal mucosa has been subjected to further purification and identification. Although this inhibitor moved as a single spot on thin-layer chromatography in a number of different solvent systems, it proved to be a mixture of free carboxylic acids whose relative composition was similar in different batches. Detailed studies involving the use of high-pressure liquid chromatography, combined gas chromatography-mass spectrometry, high-field 360 MHz proton nuclear magnetic resonance spectroscopy, fast atom bombardment mass spectrometry and other techniques established that the inhibitor was a mixture of carboxylic acids of the following identity and relative composition (the major components comprising 92% of the total fatty acids): palmitic acid, 14.8%; palmitoleic acid, 3.6%; stearic acid, 7.0%; oleic acid, 21.0%; linoleic acid, 27.6% arachidonic acid, 18.0%. Mixtures of authentic fatty acids of the same relative concentration showed inhibition of peroxidation, comparable with the purified inhibitor from intestinal mucosa. A study of the inhibitory activity of the components of the mixture using malonaldehyde estimation, diene conjugation and arachidonic acid estimation showed that the inhibitory activity was due to palmitoleic and oleic acids only, the latter being the major component.

Animals↗

An unidentified inhibitor of lipid peroxidation in intestinal mucosa.

Lipid peroxidation in vitro was tested by malonaldehyde production in gastrointestinal mucosa and compared with other tissues. It was observed that gastrointestinal mucosa was resistant to both non-enzymatic and enzymatic lipid peroxidation. This was due to the presence of an inhibitor of lipid peroxidation in the membranous fractions of intestinal mucosa. This inhibitor was capable of inhibiting other recognised peroxidation systems, such as liver mitochondria. This effect was confirmed by measurement of diene conjugation and utilisation of arachidonic acid as other markers of peroxidation, in addition to malonaldehyde production. Preliminary characterisation of this inhibitor revealed that it is resistant to proteolysis, non-diffusable and extractable from membranes by organic solvents. It was partially purified by methanol extraction of the mucosa and by three successive preparative thin-layer chromatography steps. The purified material gave a single spot on thin-layer chromatography, using a number of different solvent systems. Mobility of the inhibitor on thin-layer chromatography was different from that of authentic tocopherol, and it was present in the intestine of vitamin-E-deficient animals. These results suggest that the resistance of intestinal mucosa to lipid peroxidation is due to the presence of a novel inhibitor which is lipidic in nature.

Animals↗

Left ventricular oxygen extraction during submaximal and maximal exertion in ponies.

1. Left ventricular (LV) myocardial O2 extraction was studied in five healthy ponies which had catheters implanted in the great cardiac vein and main pulmonary artery 15-30 days before the study. The abdominal aorta was percutaneously catheterized to sample arterial blood. 2. In addition, phasic LV and aortic pressures, LV dP/dtmax and rate-pressure product were also studied; dP/dtmax is the maximal rate of rise of the left ventricular pressure during the isovolumic phase, and is considered an index of myocardial contractility. Measurements were made at rest (control) and during adenosine infusion (3 mumol kg-1 min-1) at rest, moderate exercise (heart rate 169 +/- 10 beats min-1), heavy exercise (heart rate 198 +/- 7 beats min-1), maximal exercise (heart rate 232 +/- 7 beats min-1), and adenosine infusion (3 mumol kg-1 min-1) during maximal exercise (heart rate 230 +/- 6 beats min-1). 3. In resting ponies, LV arterial to coronary venous O2 content difference (delta LVa-v O2) was 8.9 +/- 0.5 ml dl-1 and O2 extraction was 59.9 +/- 2.2%. Adenosine infusion at rest decreased delta LVa-v O2 and O2 extraction precipitously (2.6 ml dl-1 and 14.3 +/- 1.7%, respectively), thereby indicating superfluous LV myocardial perfusion. 4. Moderate, heavy and maximal exercise increased delta LVa-v O2 to 185, 194 and 218% of its control value and O2 extraction rose to 71 +/- 2, 75 +/- 1.5 and 78 +/- 0.9%, respectively. The widening of the delta LVa-v O2 gradient was due to the increased arterial O2 content during exercise. 5. Combining these observations with equine myocardial perfusion, the LV O2 consumption was calculated to be 7.8, 47.9 and 103.6 ml min-1 100 g-1 at rest, moderate and maximal exercise. In order to achieve the 13.4-fold increase in LV O2 consumption, the LV perfusion rose only 6-fold; the rest being met by widening the delta LVa-v O2. 6. Adenosine infusion during maximal exercise decreased delta LVa-v O2 and O2 extraction (10.7 +/- 1 ml dl-1 and 45%, respectively; P less than 0.0001). This indicated that coronary vasodilator capacity was not being completely expended in maximally exercising ponies. It is concluded that coronary circulation is unlikely to be a limiting factor to further exertion in ponies. Organ/tissue perfusion studies in exercising ponies have demonstrated that of all working muscles, the left ventricular (LV) myocardium received the highest level of blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗

Diaphragmatic O2 and lactate extraction during submaximal and maximal exertion in ponies.

Diaphragmatic O2 and lactate extraction were studied in 10 healthy ponies at rest and during treadmill exercise. The phrenic vein was aseptically catheterized via a lateral thoracotomy 8-35 days before the study. Arterial and phrenic venous blood samples were obtained simultaneously at rest and at 30-s intervals during 4 min of exertion. Three levels of exertion were studied (moderate, 10 mi/h; heavy, 15 mi/h; maximal, 20 mi/h), and a rest period of at least 90 min was allowed between them. Each pony was studied twice at least 2-3 days apart. At rest the diaphragmatic venous PO2, O2 saturation, arteriovenous O2 content difference, and O2 extraction were 43.2 +/- 2.0 Torr, 76.1 +/- 3.2%, 3.14 +/- 0.43 ml/dl, and 23.60 +/- 3.61%, respectively. Significant decrease in phrenic venous PO2 and O2 saturation occurred within 30 s of exercise. Phrenic venous PO2 decreased to 20.3 +/- 1.0, 18.9 +/- 1.1, and 15.4 +/- 0.9 Torr at 120 s of moderate, heavy, and maximal exercise, respectively. Corresponding values of phrenic venous O2 saturation were 33.6 +/- 2.2, 25.8 +/- 2.1, and 17.9 +/- 0.5%, respectively. Diaphragmatic arteriovenous O2 content difference expanded to 13.11 +/- 0.49, 15.00 +/- 0.60, and 16.90 +/- 0.60 ml/dl at 120 s of moderate, heavy, and maximal exercise, respectively, as O2 extraction rose to 65.93 +/- 1.98, 73.90 +/- 1.99, and 80.95 +/- 0.47%, respectively. During heavy and maximal exercise, the diaphragmatic venous lactate concentration remained similar to the arterial concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗

Costal vs. crural diaphragmatic blood flow during submaximal and near-maximal exercise in ponies.

The present study was carried out 1) to compare blood flow in the costal and crural regions of the equine diaphragm during quiet breathing at rest and during graded exercise and 2) to determine the fraction of cardiac output needed to perfuse the diaphragm during near-maximal exercise. By the use of radionuclide-labeled 15-micron-diam microspheres injected into the left atrium, diaphragmatic and intercostal muscle blood flow was studied in 10 healthy ponies at rest and during three levels of exercise (moderate: 12 mph, heavy: 15 mph, and near-maximal: 19-20 mph) performed on a treadmill. At rest, in eucapnic ponies, costal (13 +/- 3 ml.min-1.100 g-1) and crural (13 +/- 2 ml.min-1.100 g-1) phrenic blood flows were similar, but the costal diaphragm received a much larger percentage of cardiac output (0.51 +/- 0.12% vs. 0.15 +/- 0.03% for crural diaphragm). Intercostal muscle perfusion at rest was significantly less than in either phrenic region. Graded exercise resulted in significant progressive increments in perfusion to these tissues. Although during exercise, crural diaphragmatic blood flow was not different from intercostal muscle blood flow, these values remained significantly less (P less than 0.01) than in the costal diaphragm. At moderate, heavy, and near-maximal exercise, costal diaphragmatic blood flow (123 +/- 12, 190 +/- 12, and 245 +/- 18 ml.min-1.100 g-1) was 143%, 162%, and 162%, respectively, of that for the crural diaphragm (86 +/- 10, 117 +/- 8, and 151 +/- 14 ml.min-1.100 g-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Costal diaphragmatic O2 and lactate extraction in laryngeal hemiplegic ponies during exercise.

Diaphragmatic O2 and lactate extraction were examined in seven healthy ponies during maximal exercise (ME) carried out without, as well as with, inspiratory resistive breathing. Arterial and diaphragmatic venous blood were sampled simultaneously at rest and at 30-s intervals during the 4 min of ME. Experiments were carried out before and after left laryngeal hemiplegia (LH) was produced. During ME, normal ponies exhibited hypocapnia, hemoconcentration, and a decrease in arterial PO2 (PaO2) with insignificant change in O2 saturation. In LH ponies, PaO2 and O2 saturation decreased well below that in normal ponies, but because of higher hemoglobin concentration, arterial O2 content exceeded that in normal ponies. Because of their high PaCO2 during ME, acidosis was more pronounced in LH animals despite similar lactate values. Diaphragmatic venous PO2 and O2 saturation decreased with ME to 15.5 +/- 0.9 Torr and 18 +/- 0.5%, respectively, at 120 s of exercise in normal ponies. In LH ponies, corresponding values were significantly less: 12.4 +/- 1.3 Torr and 15.5 +/- 0.7% at 120 s and 9.8 +/- 1.4 Torr and 14.3 +/- 0.6% at 240 s of ME. Mean phrenic O2 extraction plateaued at 81 and 83% in normal and LH animals, respectively. Significant differences in lactate concentration between arterial and phrenic-venous blood were not observed during ME. It is concluded that PO2 and O2 saturation in the phrenic-venous blood of normal ponies do not reach their lowest possible values even during ME. Also, the healthy equine diaphragm, even with the added stress of inspiratory resistive breathing, did not engage in net lactate production.

Animals↗

Effect of splenectomy on exercise-induced pulmonary and systemic hypertension in ponies.

Large increases in systemic and pulmonary arterial pressures of exercising healthy ponies have been observed. Because exercise causes a considerable increase in PCV of ponies, we examined the effect of splenectomy on exercise-induced changes in systemic and pulmonary pressures. These pressures (taken with catheter-tip micromanometers) and indicator dilution cardiac output were determined on 9 healthy ponies that had undergone splenectomy 4 to 9 weeks before the study. Data obtained at rest and during submaximal (10.5 to 11.0 mph) and maximal (14 to 15 mph) exercise from these ponies were compared with similar data from clinically normal ponies. Following splenectomy, PCV increased by only 4 vol% during maximal exercise, but cardiac output of splenectomized ponies reached values similar to those of clinically normal ponies. Despite this similarity in cardiac output, the systemic and pulmonary arterial pressures of exercising splenectomized ponies increased to significantly lower levels than those in clinically normal ponies (P less than 0.01); total pulmonary vascular resistance and total peripheral resistance decreased to values significantly less than those in clinically normal ponies (P less than 0.01). Thus, it appears that increases in blood viscosity induced by increases in PCV may contribute substantially to the pulmonary and systemic hypertension of exercise in clinically normal ponies.

Animals↗