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L Vico

Publications and source records attributed to L Vico.

At least 37 records · Page 2Linked to original sources
PubMed2000

Space flight is associated with rapid decreases of undercarboxylated osteocalcin and increases of markers of bone resorption without changes in their circadian variation: observations in two cosmonauts.

BACKGROUND: Microgravity induces bone loss by mechanism(s) that remain largely unknown. METHODS: We measured biochemical markers related to bone remodeling in two cosmonauts before, during, and after 21- and 180-day space flights, respectively. RESULTS: During both flights, type I procollagen propeptide and bone alkaline phosphatase decreased as early as 8 days after launch. Undercarboxylated osteocalcin percentage increased early and remained high during both flights. Vitamin K supplementation restored carboxylation of osteocalcin during the long-term flight. Urinary and serum C-telopeptide of type I collagen (CTX) increased as early as day 8 of the flights; the increase was greater in serum than in urine. Pyridinoline, free deoxypyridinoline, and N-telopeptide increased less than CTX during the short-term space flight. The circadian rhythm of bone resorption assessed by urine CTX and free deoxypyridinoline was not altered by microgravity. CONCLUSION: Vitamin K metabolism or action and bone remodeling may be altered in cosmonauts.

Adult↗
PubMed1999

Effects of static or dynamic mechanical stresses on osteoblast phenotype expression in three-dimensional contractile collagen gels.

Studies performed at tissular (three-dimensional, 3-D) or cellular (two-dimensional, 2-D) levels showed that the loading pattern plays a crucial role in the osteoblastic physiology. In this study, we attempted to investigate the response of a 3-D osteoblastic culture submitted to either no external stress or static or dynamic stresses. Rat osteosarcoma cells (ROS 17/2.8) were embedded within collagen type I lattices and studied for 3 weeks. Entrapment and proliferation of cells within the hydrated collagen gel resulted in the generation of contractile forces, which led to contraction of the collagen gel. We used this ability to evaluate the influence of three modes of mechanical stresses on the cell proliferation and differentiation: (1) the freely retracted gels (FRG) were floating in the medium, (2) the tense gels (TG) were stretched statically and isometrically, with contraction prevented in the longitudinal axis, and (3) the dynamic gels (DG) were floating gels submitted to periodic stresses (50 or 25 rpm frequency). Gels showed maximum contraction at day 12 in 50 rpm DG, followed by 25 rpm DG, then FRG (88%, 81%, 70%, respectively) and at day 16 in TG (33%). The proliferation rate was greater in TG than in FRG (+52%) but remained low in both DGs. Gel dimensions were related to the collagen concentration and on a minor extent to cell number. Cells in DG appeared rounder and larger than in other conditions. In TG, cells were elongated and oriented primarily along the tension axis. Scanning electron microscopy (SEM) showed that tension exerted by cells in TG led to reorientation of collagen fibers which, in turn, determined the spatial orientation and morphology of the cells. Transmission electron microscopy (TEM) performed at maximum proliferation showed a vast majority of cells with a distended well-developed RER filled with granular material and numerous mitochondria. Alkaline phosphatase activity peaked close to the proliferation peak in FRG, whereas in TG, a biphasic curve was observed with a small peak at day 4 and the main peak at day 16. In DG, this activity was lower than in the two other conditions. A similar time course was observed for alkaline phosphatase gene expression as assessed by Northern blots. Regardless of the conditions, osteocalcin level showed a triphasic pattern: a first increase at day 2, followed by a decrease from day 4 to 14, and a second increase above initial values at day 18. Microanalysis-x indicated that mineralization occurred after 14 days and TEM showed crystals within the matrix. We showed that static and dynamic mechanical stresses, in concert with 3-D collagen matrices, played a significant role on the phenotypic modulation of osteoblast-like cells. This experimental model provided a tool to investigate the significance and the mechanisms of mechanical activity of the 3-D cultured osteoblast-like cells.

Alkaline Phosphatase↗
PubMed1999

Effects of centrifuging at 2g on rat long bone metaphyses.

Hypergravity may be considered as a means of counteracting the deleterious effects of microgravity on bone tissue. The effects of exposure to 4 days of hypergravity provided by centrifuging, on bone tissue were studied using histomorphometry. Young 53-day-old male Sprague Dawley rats were randomly divided into a centrifuged group (2g, n = 10), a rotated group (ROTATE, n = 6) of rats exposed to 1.03 g placed in cages near the centre of rotation of the centrifuge and a stationary control group (CONTROL, n = 10). The body mass of the 2g rats was decreased by this experience by 16% compared to CONTROL. The width of the tibial growth plate of 2g was decreased. In two out of ten 2g rats, the hypertrophic zone was injured. In both the tibial and humeral primary (1 degrees ) spongiosae, a reduced 1 degrees spongiosa width (-35% and -24%, ROTATE versus CONTROL respectively; -37% and -41%, 2g versus CONTROL respectively) associated with bone gain (+27% for tibia and humerus ROTATE versus CONTROL; + 16% and +20%, 2g versus CONTROL respectively) was observed in both ROTATE and 2g. In the tibial secondary (2 degrees) spongiosa, bone mass was increased in the 2g (+13% 2g versus CONTROL) rats due to thicker trabeculae, but was decreased in ROTATE rats (-12% versus CONTROL) due to thinner trabeculae. The parameters of formation and resorption activities were stimulated in the 2g and ROTATE groups, the formation activity being more enhanced in 2g. No structural changes were observed in the humeral 2 degrees spongiosa in any of the groups. Numeral bone formation parameters were decreased in 2g and ROTATE but resorption activity was increased in 2g and decreased in ROTATE compared to CONTROL. In conclusion, as early as the 4th day, 2g hypergravity induced reduced endochondral bone formation and increased cancellous bone mass. Rotation led to mixed results including reduced endochondral bone formation, increased bone volume in the 1 degrees spongiosa and bone loss in the 2 degrees spongiosa.

Animals↗
PubMed1999

Recurrence of vertebral fracture with cyclical etidronate therapy in osteoporosis: histomorphometry and X-Ray microanalysis evaluation.

In an open prospective study, we evaluated differences between patients with (wRVF group) and without recurrence of vertebral fracture (woRVF group) during cyclical etidronate therapy for osteoporosis. Thirty-two patients (age 64 +/- 1.8 years) characterized by at least one osteoporotic VF were treated during 1 year. At baseline, body mass index was significantly lower (23.3 +/- 0.6 vs. 26.9 +/- 1.0 kg/m2, p< 0.05), the number of previous VFs was higher (4.0 +/- 0. 4 vs. 2.4 +/- 0.4, NS), and patients were older in the wRVF group as compared with the woRVF group (67.8 +/- 3 vs. 62.6+/- 2.2 year, NS). Trabecular bone volume (11.6 +/- 1.2 vs. 15 +/- 0.9%, p< 0.05) and trabecular number (1.06 +/- 0.08 vs. 1.27 +/- 0.05, p < 0.05) were significantly lower in the wRVF group. None of the baseline resorptive variables differed, whereas the bone formation rate (BFR) was 2-fold lower in the wRVF group (p< 0. 05). After 1 year of treatment, osteoclast number, active eroded surfaces, and resorption depth dramatically decreased in both groups (p< 0. 01). To a lesser extent, the mineral apposition rate and serum alkaline phosphatase level were significantly reduced (p< 0.05). No impaired mineralization was observed. Using X-ray microanalysis, we found no abnormality in bone mineral but a significant increase of the calcium/phosphorus ratio during treatment in the wRVF group. Our results demonstrate that recurrence of VFs within the first year of cyclical etidronate therapy was related neither to a lack of histologic response to the treatment nor induction of an abnormality of mineralization. VFs were more likely in the presence of a decreased BFR and lower trabecular connectivity, providing support for treating osteoporotic patients with etidronate early in the course of the disease.

Adult↗
PubMed1999

Bisphosphonate effects in rat unloaded hindlimb bone loss model: three-dimensional microcomputed tomographic, histomorphometric, and densitometric analyses.

The effects of antiresorptive drugs on bone loss remain unclear. Using three-dimensional microtomography, dual X-ray/densitometry, and histomorphometry, we evaluated tiludronate effects in the bone loss model of immobilization in tail-suspended rats after 7, 13, and 23 days. Seventy-eight 12-week-old Wistar male rats were assigned to 13 groups: 1 baseline group, and for each time point, 1 control group treated with vehicle and three tail-suspended groups treated with either tiludronate (0.5 or 5 mg/kg) or vehicle, administered s. c. every other day, during the last week before sacrifice. In primary spongiosa (ISP), immobilization-induced bone loss plateaued after day 7 and was prevented by tiludronate. In secondary spongiosa (IISP), bone loss appeared at day 13 with a decrease in trabecular thickness and trabecular number (Tb.N) as assessed by three-dimensional microtomography. Osteoclastic parameters did not differ in tail-suspended rats versus control rats, whereas bone formation showed a biphasic pattern: after a marked decrease at day 7, osteoblastic activity and recruitment normalized at days 13 and 23, respectively. At day 23, the 80% decrease in bone mass was fully prevented by high-dose tiludronate with an increase in Tb.N without preventing trabecular thinning. In summary, at day 7, tiludronate prevented bone loss in ISP. After day 13, tiludronate prevented bone loss in ISP and IISP despite a further decrease in bone formation. Thus, the preventive effects of tiludronate in this model may be related to the alteration in bone modeling with an increase in Tb.N in ISP and subsequently in IISP.

Analysis of Variance↗
PubMed1998

Rotating-wall vessels, promising bioreactors for osteoblastic cell culture: comparison with other 3D conditions.

Osteoblastic cells cultured on microcarriers in bioreactors are a potentially useful tool to reproduce the in vivo three-dimensional (3D) bone network. The aim is to compare different types of 3D and two-dimensional (2D) osteoblastic culture. ROS17/2.8 cells are cultured in a bioreactor (rotating-wall vessel) or in two kinds of control (3D petri dish, 3D Percoll) and on two types of microcarrier (Cytodex 3 and Biosilon). Growth and morphology are determined by cell count and SEM, and differentiation is determined by dosage of alkaline phosphatase (ALP) activity and northern blots (ALP and osteocalcin (OC)). SEM shows that Biosilon microcarriers are the best substrate. Proliferation in the RWV and 3D petri dish is still in the exponential phase, whereas growth in the 2D culture reaches a plateau after eight days of culture. ALP activity and the ALP and OC mRNA levels are similar at day 8 for both the RWV and 3D petri dish. However, at day 10, cells are more differentiated in the RWV. The study shows that osteoblasts are both proliferate and differentiate in 3D structures. A BrDU immunocytochemical approach shows that only the cells in the periphery of the aggregates proliferate. Therefore the bioreactor may be a suitable tissue culture model for investigation of growth and differentiation processes in tissue engineering.

Animals↗
PubMed1998

Energy and substrate metabolism during a 42-day bed-rest in a head-down tilt position in humans.

Microgravity-induced changes in body composition (decrease in muscle mass and increase in fat mass) and energy metabolism were studied in seven healthy male subjects during a 42-day bed-rest in a head-down tilt (HDT) position. Resting energy expenditure (REE), fat and glucose oxidation were estimated by indirect calorimetry on days 0, +8 and +40 of the HDT period. Assessments were performed both in post-absorptive conditions and following two identical test meals given at 3-h intervals. Body composition (dual x-ray absorptiometry) was measured on days 0, +27, +42. Mean post-absorptive lipid oxidation decreased from 53 (SEM 8) mg x min(-1) (day 0) to 32 (SEM 10) mg x min(-1) (day 8, P = 0.04) and 36 (SEM 8) mg x min(-1) (day 40, P = 0.06). Mean post-absorptive glucose oxidation rose from 126 (SEM 15) mg x min(-1) (day 0) to 164 (SEM 14) mg x min(-1) (day 8, P = 0.04) and 160 (SEM 20) mg x min(-1) (day 40, P = 0.07). Mean fat-free mass (FFM) decreased between days 0 and 42 [58.0 (SEM 1.8) kg and 55.3 (SEM 1.7) kg, P < 0.01] while fat mass increased without reaching statistical significance. The mean REE decreased from 1688 (SEM 50) kcal x day(-1) to 1589 (SEM 42) kcal x day(-1) (P = 0.056). Changes in REE were accounted for by changes in FFM. Mean energy intake decreased from 2532 (SEM 43) kcal x day(-1) to 2237 (SEM 50) kcal x day(-1) (day 40, P < 0.01) with only a minor decrease in the proportion of fat. We concluded that changes in fat oxidation at the whole body level can be found during HDT experiments. These changes were related to the decrease in FFM and could have promoted positive fat balance hence an increase in fat mass.

Adult↗
PubMed1998

Effects of gravitational changes on the bone system in vitro and in vivo.

Spaceflight data obtained on bone cells, rodents, and humans are beginning to shed light on the importance of gravitational loading on the skeletal system. The space environment is a relevant model to explore the bone cell response to minimal strains. However, whether there is a direct effect of gravity on the cell rather than changes related to lack of convection forces in cell cultures performed in microgravity is unknown. In vitro studies carried out using osteoblastic cell cultures in space show changes in cell shape, suggesting that cell attachment structures as well as cytoskeleton reorganization might be involved. Valuable information is expected from in vitro models of an increase or decrease in mechanical stress in order to identify the different pathways of mechanoreception and mechanotransduction in the osteoblastic lineage. Results obtained from both humans and rodents after spaceflights indicated that bone mass changes are site specific rather than evenly distributed throughout the skeleton, thus emphasizing the need to perform measurements at different bone sites: weight- and non-weight-bearing bones, and cancellous and cortical envelopes. Bone mass measurements and biochemical parameters of bone remodeling are currently under evaluation in cosmonauts. Histomorphometric studies of bones from rats after space missions of various periods provided the time course of the cancellous bone cellular events: transient increase in resorption and sustained decrease in bone formation. The underlying bone loss occurred first in weight-bearing bones and later in less weight-bearing bones. During the postflight period, time required to recover the lost bone was greater than the mission length. Thus, the postflight period deserves more attention than it is currently receiving. On earth, the rat tail-suspension model is currently used to mimic spaceflight-induced bone loss. Data from the model confirmed the impairment of osteoblastic activity and showed an alteration in osteoblast recruitment with skeletal unloading. However, this model needs to be further validated.

Adaptation, Physiological↗
PubMed1998

Hindlimb unloading in rat decreases preosteoblast proliferation assessed in vivo with BrdU incorporation.

Immobilization affects bone formation. However, the mechanisms regulating the decrease in osteoblast recruitment remain unclear. The aim of our study was to determine in vivo osteoblastic proliferation after short-term immobilization among the different bone compartments. Twelve Wistar 5-wk-old rats were assigned to two groups: six tail-suspended animals for 6 days and their six age-related controls. Osmotic minipumps, each containing 40 mg of bromodeoxyuridine (BrdU), were implanted intraperitoneally at day 4 until euthanasia. Histomorphometric measurements found a significantly lower bone volume in primary (ISP, -22%) and secondary spongiosa (IISP, -37%) in unloaded rats compared with their age-related controls. BrdU immunohistochemistry showed that the proliferation capacity of osteogenic precursors in ISP (-29%) and preosteoblasts in IISP (-80%) and in periosteum as well as bone marrow cells (-40%) was lowered by unloading. We demonstrated in vivo for the first time that 6-day tail suspension induced a significant decrease in proliferation of periosteal and trabecular preosteoblasts in ISP and IISP as well as in bone marrow cells.

Animals↗
PubMed1998

Space-related bone mineral redistribution and lack of bone mass recovery after reambulation in young rats.

This study reports the effects of a 14-day spaceflight followed by a 14-day reambulation period on bones of 56-day-old male rats compared with synchronous (S) and vivarium (V) control animals. Femur, tibia, and humerus bone mineral densities (BMD); bone calcium and phosphorus concentrations ([Ca2+] and [P]), measured by X-ray microanalysis (XRM), on tibia, vertebra, and calvaria; and histomorphometric data on proximal primary and secondary spongiosae (I and II SP, respectively) of the tibia and humerus were measured. After the flight in flown rats (compared with S), BMD was lower in the distal femur and remained similar to S in humerus and tibia, [Ca2+] and [P] were lower in tibia II SP and higher in calvaria, tibia I SP width and II SP bone volume were lower, resorption was markedly higher in tibia II SP, and no difference in formation parameters was observed. After reambulation, BMD was lower in long bones of both flight and S groups compared with V. Bone loss appeared in humeral II SP and worsened in tibial II SP in flown rats. Tibial formation parameters were higher in flown rats compared with V and S, indicating the onset of an active recovery. Tibial XRM [Ca2+] and [P] in flown rats remained below control levels.

Animals↗
PubMed1998

Energy and water metabolism, body composition, and hormonal changes induced by 42 days of enforced inactivity and simulated weightlessness.

Inactivity causes profound deleterious changes. We investigated in eight healthy men the impact of a 42-day head-down bed rest (HDBR) on energy and water metabolism and their interrelationships with body composition (BC) and catabolic and anabolic hormones. Total energy expenditure (TEE), total body water, water turnover, and metabolic water formation were assessed by the doubly labeled water method 15 days before and for the last 15 days of HDBR. Resting energy expenditure was determined by indirect calorimetry, and BC was determined by dual energy x-ray absorptiometry. Urinary excretion of cortisol, GH, normetanephrine, metanephrine, urea, and creatinine were measured daily. HDBR resulted in significant reductions in body weight (2%), total body water (5%), metabolic water (17%), and lean body mass (LBM; 4%), but fat mass and water turnover did not change. Segmental BC showed a decreased LBM in legs and trunk, whereas fat mass increased, no significant changes were noted in the arms. The hydration of LBM was unchanged. TEE and energy intake decreased significantly (20% and 13%), whereas resting energy expenditure was maintained. Expenditure for physical activity dropped by 39%. Subjects were in energy balance during HDBR, whereas it was negative during the control period (-1.5 MJ/day). There were decreases in urinary normetanephrine (23%) and metanephrine (23%), but urinary cortisol (28%; weeks 2 and 3), GH (75%; weeks 2-4), and urea (15%; weeks 3 and 4) increased. It was concluded that during prolonged HDBR no relevant modifications in water metabolism were triggered. BC changes occurred in the nonexercised body segments, and the reduction in TEE was due to inactivity, not to LBM loss. Moreover, body weight alone does not accurately reflect the subject's energy state, and energy balance alone could not explain the body weight loss, which involves a transient metabolic stress.

Absorptiometry, Photon↗
PubMed1997

Effects of intermittent or continuous gravitational stresses on cell-matrix adhesion: quantitative analysis of focal contacts in osteoblastic ROS 17/2.8 cells.

The relationship between cell morphology and cell metabolism and the role of mechanical load in bone remodeling is well known. Mechanical stimulation induces changes in the shape of osteoblasts, probably mediated by reorganization of focal contacts. We studied the influence of gravity (Gz) variations occurring during parabolic flight on osteoblast focal adhesion of ROS 17/2.8 osteosarcoma cells subjected to 15 or 30 parabolic flights. Significant flight-induced shape changes consisted of decreased cell area associated with focal contact plaque reorganization. Identical durations of continuous mechanical stress induced by centrifugation (2 Gz) or clinorotation (Gz randomization) had no major effect on cell focal adhesion. ROS 17/2.8 G2/M synchronization by treatment with nocodazole inhibited the flight-induced decrease in adhesion parameters. We concluded that ROS 17/2.8 cells are sensitive to Gz switches and that their adaptation is at least dependent on microtubule function.

Animals↗
PubMed1997

Quantitation of cell-matrix adhesion using confocal image analysis of focal contact associated proteins and interference reflection microscopy.

We have developed an approach for the quantitation of vinculin, a focal contact associated protein, based on a multimodal confocal microscopy and image analysis. Vinculin spot distribution was imaged in confocal fluorescence microscopy and the corresponding focal contacts were imaged in confocal interference reflection microscopy. These images were analyzed with a SAMBA image cytometer. The image analysis program provided 12 morphometric features describing cellular area, shape, and proportions of vinculin spots as well as six topographical features describing the distribution of vinculin and the relative overlap of vinculin and focal contacts. This approach was applied to the study of rat osteosarcoma cells submitted to mechanical stresses: successions of 2g and 0g accelerations during a series of parabolic flights. The measured features were assessed by means of correlation analysis and stepwise discriminant analysis. After correlation analysis, only ten parameters were retained. Quantitation of cell morphological parameters indicated that cell area was significantly affected by gravitational stresses as well as vinculin distribution. Cell area was reduced by 50% and vinculin spots were restricted to cell periphery. Cell adhesion measured by IRM decreased significantly in the first part of the flight and remained stable at the end of the flight. These results suggest that cell-matrix adhesion is affected by gravitational stresses. Image analysis provides useful tools to investigate focal adhesion re-organization under different physiological stimuli.

Animals↗
PubMed1997

Demonstration of feasibility of automated osteoblastic line culture in space flight.

There is a large body of evidence that microgravity- or immobilization-induced bone loss is mainly related to osteoblastic cell impairment. Osteoblasts are sensitive to increased mechanical stress and could therefore be responsible for unloading-induced bone changes. However, the nature of osteoblast involvement remains unclear. The effects of the space environment on cells have been studied extensively, but little information about anchorage-dependent cell cultures of the 25 different cell types flown in space has been published. We studied the effects of long-term weightlessness on the cell shape of cultured osteoblasts during the Russian Bion 10 space-flight. This experiment required the development of special automatic culture devices (the plunger-box culture system) finalized with the constructors. Multiple feasibility experiments were performed to allow osteoblast culture for 6 days in microgravity. The study revealed plunger-box biocompatibility; optimization of ROS 17/2.8 (mammalian adherent cells) culture under closed conditions (without gas exchange); and transport of viable cells for 5 days. During the 6 days of microgravity, the growth curves of ground controls and cells in space were roughly similar. Alkaline phosphatase activity was enhanced twofold in microgravity. ROS 17/2.8 cell morphology began to change significantly after 4 days of microgravity; they became rounder and covered with microvilli. At the end of the flight, the cells exhibited mixed morphological types, piling cells, stellar shape, and spread out cells, resembling ground controls or 1g flight controls (centrifuge). We demonstrated that ROS 17/2.8 cells were viable during a 6 day automatic culture in space and were sensitive to space related conditions. They adapted their structure and function to this environment, characterized by loss of mechanical stimuli.

Alkaline Phosphatase↗
PubMed1997

Effects of 1- and 6-month spaceflight on bone mass and biochemistry in two humans.

The bone mineral density and the biochemical parameters exploring bone cell activities were analyzed in two cosmonauts who spent 1 and 6 months, respectively, in the Russian MIR station. Measurements were performed before the flight, after the flight, and after a recovery period. At the end of the first month, peripheral QCT measurements indicated a slight decrease of trabecular bone mass in the distal tibial metaphysis. However, after 6 months of spaceflight, a more marked loss of trabecular and cortical bones was observed in the tibia, and was still significant after 6 month recovery in the trabecular compartment, whereas a decrease was no longer observed in the cortical envelope. No change was observed in either compartment of the distal radius at any time. Ultrasound BUA of the calcaneus was greatly reduced by the first month, followed by a more dramatic decrease after month 6. Ultrasound SOS detected no change. Parameters reflecting bone formation activity appeared to be depressed after both missions. In contrast, no dramatic change in resorption parameters was observed, except for a trend toward an increase in pyridinoline. In conclusion, the lower weight-bearing bones appeared more sensitive than the upper ones in terms of spaceflight-induced bone loss. This probably explained the absence of marked systemic biochemical data changes. This study further suggests that recovery in the tibial trabecular compartment 6 months after landing was not completed after a 6 month mission.

Adult↗
PubMed1996

The insertion of the extensor digitorum tendon on the proximal phalanx.

Review of the literature reveals that the relationship between the extensor digitorum muscle tendon to the proximal phalanx and the metacarpophalangeal joint capsule remains unclear. The present study presents data about these relationships and consists of three parts: dissection of the region, high-gradient magnetic resonance imaging, and functional study. A total of 50 hands were used. Dissection was performed on 30, magnetic resonance studies were performed on 10, and the remaining 10 hands were used for the functional analysis. Dissection did not reveal an insertion of the extensor digitorum tendon on the base of the proximal phalanx. An extension of the dorsal part of the metacarpophalangeal joint capsule running proximally toward the palmar side of the extensor tendon was observed in eight hands. In the remaining 22 hands, only loose connective tissue was found between the articular capsule and the tendon. The development of this tissue was variable. These observations were correlated using a 7T magnetic resonance installation. The results of the functional study showed that hyperextension of the proximal phalanx increased after resection of the metacarpophalangeal structures lying under the extensor tendon. In conclusion, no real tendinous insertion of the extensor digitorum tendon on the base of the proximal phalanx could be found. Loose connective tissue was observed between the metacarpophalangeal joint capsule and the palmar aspect of the tendon, which seemed to play a secondary role in the extension of the proximal phalanx.

Biomechanical Phenomena↗