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Article ; Online: Circadian rhythm of intraocular pressure.

Ikegami, Keisuke

The journal of physiological sciences : JPS

2024 Volume 74, Issue 1, Page(s) 14

Abstract: Intraocular pressure (IOP) plays a crucial role in glaucoma development, involving the dynamics of aqueous humor (AH). AH flows in from the ciliary body and exits through the trabecular meshwork (TM). IOP follows a circadian rhythm synchronized with the ... ...

Abstract	Intraocular pressure (IOP) plays a crucial role in glaucoma development, involving the dynamics of aqueous humor (AH). AH flows in from the ciliary body and exits through the trabecular meshwork (TM). IOP follows a circadian rhythm synchronized with the suprachiasmatic nucleus (SCN), the circadian pacemaker. The SCN resets peripheral clocks through sympathetic nerves or adrenal glucocorticoids (GCs). IOP's circadian rhythm is governed by circadian time signals, sympathetic noradrenaline (NE), and GCs, rather than the local clock. The activity of Na
MeSH term(s)	Humans ; Intraocular Pressure ; Glaucoma ; Trabecular Meshwork ; Aqueous Humor/physiology ; Circadian Rhythm/physiology ; Glucocorticoids
Chemical Substances	Glucocorticoids
Language	English
Publishing date	2024-03-02
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	2234472-X
ISSN	1880-6562 ; 1880-6546
ISSN (online)	1880-6562
ISSN	1880-6546
DOI	10.1186/s12576-024-00905-8
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Article ; Online: Suppression of trabecular meshwork phagocytosis by norepinephrine is associated with nocturnal increase in intraocular pressure in mice.

Ikegami, Keisuke / Masubuchi, Satoru

Communications biology

2022 Volume 5, Issue 1, Page(s) 339

Abstract: Intraocular pressure (IOP) is an important factor in glaucoma development, which involves aqueous humor (AH) dynamics, with inflow from the ciliary body and outflow through the trabecular meshwork (TM). IOP has a circadian rhythm entrained by sympathetic ...

Abstract	Intraocular pressure (IOP) is an important factor in glaucoma development, which involves aqueous humor (AH) dynamics, with inflow from the ciliary body and outflow through the trabecular meshwork (TM). IOP has a circadian rhythm entrained by sympathetic noradrenaline (NE) or adrenal glucocorticoids (GCs). Herein, we investigated the involvement of GC/NE in AH outflow. Pharmacological prevention of inflow/outflow in mice indicated a diurnal outflow increase, which was related to TM phagocytosis. NE showed a non-self-sustained inhibition in phagocytosis of immortalized human TM cells, but not GC. The pharmacological and reverse genetic approaches identified β1-adrenergic receptor (AR)-mediated exchange proteins directly activated by cyclic adenosine monophosphate (EPAC)-SHIP1 signal activation by ablation of phosphatidylinositol triphosphate, regulating phagocytic cup formation. Furthermore, we revealed the phagocytosis involvement in the β1-AR-EPAC-SHIP1-mediated nocturnal IOP rise in mice. These suggest that TM phagocytosis suppression by NE can regulate IOP rhythm through AH outflow. This discovery may aid glaucoma management.
MeSH term(s)	Animals ; Glaucoma ; Guanine Nucleotide Exchange Factors/metabolism ; Intraocular Pressure ; Mice ; Norepinephrine/metabolism ; Norepinephrine/pharmacology ; Phagocytosis ; Trabecular Meshwork/metabolism
Chemical Substances	Guanine Nucleotide Exchange Factors ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2022-04-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03295-y
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Article ; Online: A Survey of the Status of Methadone Switching in Japan Using a Hospital-Based Administrative Claims Database.

Imai, Shungo / Aoki, Natsumi / Ikegami, Keisuke / Kizaki, Hayato / Hori, Satoko

Journal of clinical pharmacology

2023 Volume 64, Issue 2, Page(s) 189–195

Abstract: Methadone is generally used for the management of cancer pain in patients who cannot obtain adequate analgesia from other strong opioids; however, it has a complicated and inconsistent conversion ratio from pre-switching opioid dosage to methadone. This ... ...

Abstract	Methadone is generally used for the management of cancer pain in patients who cannot obtain adequate analgesia from other strong opioids; however, it has a complicated and inconsistent conversion ratio from pre-switching opioid dosage to methadone. This issue may be pronounced in Japan because only oral tablets are commercially available. We aimed to elucidate the status of methadone switching in Japan, focusing on its dosage. Using a Japanese hospital-based administrative claims database, we included patients who switched to methadone between April 2008 and January 2021. The proportion of methadone switching completion that required more than the defined conversion ratio in the Japanese package insert (called "high-dose methadone switching") was evaluated as a primary endpoint. Other endpoints included "the duration from initiation to completion of methadone switching" and "factors affecting high-dose methadone switching by using multivariate logistic regression analysis". Of 1585 patients who received methadone, 370 were enrolled. Among those, 130 (35.1%) received high-dose methadone switching. The median duration of methadone switching completion (12 days) was longer in the high-dose methadone switching group than in other patients. Four variables were identified as factors affecting high-dose methadone switching. Younger age and outpatient status increased the risk of requiring high-dose methadone switching, whereas the concomitant use of nonsteroidal anti-inflammatory drugs and fentanyl as a pre-switching opioid decreased the risk. In conclusion, more than 30% of the patients underwent high-dose methadone switching and required long completion periods, suggesting that methadone switching remains challenging in Japan.
MeSH term(s)	Humans ; Methadone/therapeutic use ; Analgesics, Opioid ; Japan ; Neoplasms/complications ; Pain
Chemical Substances	Methadone (UC6VBE7V1Z) ; Analgesics, Opioid
Language	English
Publishing date	2023-10-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.2351
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Article ; Online: Circadian Regulation of IOP Rhythm by Dual Pathways of Glucocorticoids and the Sympathetic Nervous System.

Ikegami, Keisuke / Shigeyoshi, Yasufumi / Masubuchi, Satoru

Investigative ophthalmology & visual science

2020 Volume 61, Issue 3, Page(s) 26

Abstract: Purpose: Elevated IOP can cause the development of glaucoma. The circadian rhythm of IOP depends on the dynamics of the aqueous humor and is synchronized with the circadian rhythm pacemaker, that is, the suprachiasmatic nucleus. The suprachiasmatic ... ...

Abstract	Purpose: Elevated IOP can cause the development of glaucoma. The circadian rhythm of IOP depends on the dynamics of the aqueous humor and is synchronized with the circadian rhythm pacemaker, that is, the suprachiasmatic nucleus. The suprachiasmatic nucleus resets peripheral clocks via sympathetic nerves or adrenal glucocorticoids. However, the detailed mechanisms underlying IOP rhythmicity remain unclear. The purpose of this study was to verify this regulatory pathway. Methods: Adrenalectomy and/or superior cervical ganglionectomy were performed in C57BL/6J mice. Their IOP rhythms were measured under light/dark cycle and constant dark conditions. Ocular administration of corticosterone or norepinephrine was also performed. Localization of adrenergic receptors, glucocorticoid receptors, and clock proteins Bmal1 and Per1 were analyzed using immunohistochemistry. Period2::luciferase rhythms in the cultured iris/ciliary bodies of adrenalectomized and/or superior cervical ganglionectomized mice were monitored to evaluate the effect of the procedures on the local clock. The IOP rhythm of retina and ciliary epithelium-specific Bmal1 knockout mice were measured to determine the significance of the local clock. Results: Adrenalectomy and superior cervical ganglionectomy disrupted IOP rhythms and the circadian clock in the iris/ciliary body cultures. Instillation of corticosterone and norepinephrine restored the IOP rhythm. β2-Adrenergic receptors, glucocorticoid receptors, and clock proteins were strongly expressed within the nonpigmented epithelia of the ciliary body. However, tissue-specific Bmal1 knock-out mice maintained their IOP rhythm. Conclusions: These findings suggest direct driving of the IOP rhythm by the suprachiasmatic nucleus, via the dual corticosterone and norepinephrine pathway, but not the ciliary clock, which may be useful for chronotherapy of glaucoma.
MeSH term(s)	ARNTL Transcription Factors/metabolism ; Administration, Ophthalmic ; Adrenalectomy ; Animals ; Cells, Cultured ; Ciliary Body/drug effects ; Ciliary Body/metabolism ; Circadian Rhythm/drug effects ; Circadian Rhythm/physiology ; Corticosterone/pharmacology ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Ganglionectomy ; Immunohistochemistry ; Intraocular Pressure/physiology ; Iris/drug effects ; Iris/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Norepinephrine/pharmacology ; Period Circadian Proteins/metabolism ; Photoperiod ; Receptors, Adrenergic, beta-2/metabolism ; Receptors, Glucocorticoid/metabolism ; Superior Cervical Ganglion/surgery ; Sympathetic Nervous System/physiology ; Tonometry, Ocular
Chemical Substances	ARNTL Transcription Factors ; Bmal1 protein, mouse ; Per1 protein, mouse ; Period Circadian Proteins ; Receptors, Adrenergic, beta-2 ; Receptors, Glucocorticoid ; Corticosterone (W980KJ009P) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2020-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.61.3.26
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Article ; Online: Development of Risk Prediction Model for Grade 2 or Higher Hypocalcemia in Patients With Bone Metastasis Treated With Denosumab Plus Cholecalciferol (Vitamin D

Ikegami, Keisuke / Hashiguchi, Masayuki / Kizaki, Hayato / Yasumuro, Osamu / Funakoshi, Ryohkan / Hori, Satoko

Journal of clinical pharmacology

2022 Volume 62, Issue 9, Page(s) 1151–1159

Abstract: Denosumab-induced hypocalcemia is sometimes severe, and although a natural vitamin D/calcium combination is used to prevent hypocalcemia, some patients rapidly develop severe hypocalcemia even under supplementation. It is clinically important to predict ... ...

Abstract	Denosumab-induced hypocalcemia is sometimes severe, and although a natural vitamin D/calcium combination is used to prevent hypocalcemia, some patients rapidly develop severe hypocalcemia even under supplementation. It is clinically important to predict this risk. This study aimed to develop a risk prediction model for grade ≥2 hypocalcemia within 28 days after the first denosumab dose under natural vitamin D/calcium supplementation. Using a large database containing multicenter practice data, 2399 patients with bone metastasis who were treated with denosumab between June 2013 and May 2020 were retrospectively analyzed. Background factors in patients who developed grade ≥2 hypocalcemia within 28 days after the first denosumab dose and those who did not were compared by univariate analysis. Multivariate analysis was conducted to develop a risk prediction model. The model was evaluated for discriminant performance (receiver operating characteristic-area under the curve, sensitivity, specificity) and predictive performance (calibration slope). A total of 124 patients in the hypocalcemia group and 1191 patients in the nonhypocalcemia group were extracted. A risk prediction model consisting of sex, calcium, albumin, alkaline phosphatase, osteoporosis, breast cancer, gastric cancer, proton pump inhibitor combination, and pretreatment with zoledronic acid was developed. The receiver operating characteristic-area under the curve was 0.87. Sensitivity and specificity were 83% and 81%, respectively, and the calibration slope indicated acceptable agreement between observed and predicted risk. This model appears to be useful to predict the risk of denosumab-induced hypocalcemia and thus should be helpful for risk management of denosumab treatment in patients with bone metastases.
MeSH term(s)	Bone Density Conservation Agents/adverse effects ; Bone Neoplasms/drug therapy ; Calcium/therapeutic use ; Cholecalciferol/adverse effects ; Cholecalciferol/therapeutic use ; Denosumab/adverse effects ; Denosumab/therapeutic use ; Humans ; Hypocalcemia/chemically induced ; Hypocalcemia/drug therapy ; Hypocalcemia/prevention & control ; Retrospective Studies ; Vitamin D/therapeutic use
Chemical Substances	Bone Density Conservation Agents ; Vitamin D (1406-16-2) ; Cholecalciferol (1C6V77QF41) ; Denosumab (4EQZ6YO2HI) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-05-02
Publishing country	England
Document type	Journal Article ; Multicenter Study
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.2057
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Article ; Online: The hypothalamic-pituitary-thyroid axis and biological rhythms: The discovery of TSH's unexpected role using animal models.

Ikegami, Keisuke / Yoshimura, Takashi

Best practice & research. Clinical endocrinology & metabolism

2017 Volume 31, Issue 5, Page(s) 475–485

Abstract: Thyroid hormones (TH) are important for development, growth, and metabolism. It is also clear that the synthesis and secretion of TH are regulated by the hypothalamic-pituitary-thyroid (HPT) axis. Animal models have helped advance our understanding of ... ...

Abstract	Thyroid hormones (TH) are important for development, growth, and metabolism. It is also clear that the synthesis and secretion of TH are regulated by the hypothalamic-pituitary-thyroid (HPT) axis. Animal models have helped advance our understanding of the roles and regulatory mechanisms of TH. The animals' bodies develop through coordinated timing of cell division and differentiation. Studies of frog metamorphosis led to the discovery of TH and their role in development. However, to adapt to rhythmic environmental changes, animals also developed various endocrine rhythms. Studies of rodents clarified the neural and molecular mechanisms underlying the circadian regulation of the HPT axis. Moreover, birds have a sophisticated seasonal adaptation mechanism, and recent studies of quail revealed unexpected roles for thyroid-stimulating hormone (TSH) and TH in the seasonal regulation of reproduction. Interestingly, this mechanism is conserved in mammals. Thus, we review how animal studies have shaped our general understanding of the HPT axis in relation to biological rhythms.
MeSH term(s)	Animals ; Birds ; Hypothalamo-Hypophyseal System/physiology ; Models, Animal ; Thyroid Gland/physiology ; Thyrotropin/physiology
Chemical Substances	Thyrotropin (9002-71-5)
Language	English
Publishing date	2017-09-21
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2052339-7
ISSN	1878-1594 ; 1532-1908 ; 1521-690X
ISSN (online)	1878-1594 ; 1532-1908
ISSN	1521-690X
DOI	10.1016/j.beem.2017.09.002
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Article ; Online: FcRY is a key molecule controlling maternal blood IgY transfer to yolks during egg development in avian species.

Okamoto, Mayuko / Sasaki, Ryo / Ikeda, Koki / Doi, Kasumi / Tatsumi, Fumiya / Oshima, Kenzi / Kojima, Takaaki / Mizushima, Shusei / Ikegami, Keisuke / Yoshimura, Takashi / Furukawa, Kyohei / Kobayashi, Misato / Horio, Fumihiko / Murai, Atsushi

Frontiers in immunology

2024 Volume 15, Page(s) 1305587

Abstract: Maternal immunoglobulin transfer plays a key role in conferring passive immunity to neonates. Maternal blood immunoglobulin Y (IgY) in avian species is transported to newly-hatched chicks in two steps: 1) IgY is transported from the maternal circulation ... ...

Abstract	Maternal immunoglobulin transfer plays a key role in conferring passive immunity to neonates. Maternal blood immunoglobulin Y (IgY) in avian species is transported to newly-hatched chicks in two steps: 1) IgY is transported from the maternal circulation to the yolk of maturing oocytes, 2) the IgY deposited in yolk is transported to the circulation of the embryo via the yolk sac membrane. An IgY-Fc receptor, FcRY, is involved in the second step, but the mechanism of the first step is still unclear. We determined whether FcRY was also the basis for maternal blood IgY transfer to the yolk in the first step during egg development. Immunohistochemistry revealed that FcRY was expressed in the capillary endothelial cells in the internal theca layer of the ovarian follicle. Substitution of the amino acid residue in Fc region of IgY substantially changed the transport efficiency of IgY into egg yolks when intravenously-injected into laying quail; the G365A mutant had a high transport efficiency, but the Y363A mutant lacked transport ability. Binding analyses of IgY mutants to FcRY indicated that the mutant with a high transport efficiency (G365A) had a strong binding activity to FcRY; the mutants with a low transport efficiency (G365D, N408A) had a weak binding activity to FcRY. One exception, the Y363A mutant had a remarkably strong binding affinity to FcRY, with a small dissociation rate. The injection of neutralizing FcRY antibodies in laying quail markedly reduced IgY uptake into egg yolks. The neutralization also showed that FcRY was engaged in prolongation of half-life of IgY in the blood; FcRY is therefore a multifunctional receptor that controls avian immunity. The pattern of the transport of the IgY mutants from the maternal blood to the egg yolk was found to be identical to that from the fertilized egg yolk to the newly-hatched chick blood circulation, via the yolk sac membrane. FcRY is therefore a critical IgY receptor that regulates the IgY uptake from the maternal blood circulation into the yolk of avian species, further indicating that the two steps of maternal-newly-hatched IgY transfer are controlled by a single receptor.
MeSH term(s)	Animals ; Female ; Humans ; Infant, Newborn ; Endothelial Cells/metabolism ; Chickens ; Receptors, Fc ; Antibodies/metabolism ; Immunoglobulins
Chemical Substances	IgY ; Receptors, Fc ; Antibodies ; Immunoglobulins
Language	English
Publishing date	2024-02-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1305587
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Article ; Online: Comparative analysis reveals the underlying mechanism of vertebrate seasonal reproduction.

Ikegami, Keisuke / Yoshimura, Takashi

General and comparative endocrinology

2016 Volume 227, Page(s) 64–68

Abstract: Animals utilize photoperiodic changes as a calendar to regulate seasonal reproduction. Birds have highly sophisticated photoperiodic mechanisms and functional genomics analysis in quail uncovered the signal transduction pathway regulating avian seasonal ... ...

Abstract	Animals utilize photoperiodic changes as a calendar to regulate seasonal reproduction. Birds have highly sophisticated photoperiodic mechanisms and functional genomics analysis in quail uncovered the signal transduction pathway regulating avian seasonal reproduction. Birds detect light with deep brain photoreceptors. Long day (LD) stimulus induces secretion of thyroid-stimulating hormone (TSH) from the pars tuberalis (PT) of the pituitary gland. PT-derived TSH locally activates thyroid hormone (TH) in the hypothalamus, which induces gonadotropin-releasing hormone (GnRH) and hence gonadotropin secretion. However, during winter, low temperatures increase serum TH for adaptive thermogenesis, which accelerates germ cell apoptosis by activating the genes involved in metamorphosis. Therefore, TH has a dual role in the regulation of seasonal reproduction. Studies using TSH receptor knockout mice confirmed the involvement of PT-derived TSH in mammalian seasonal reproduction. In addition, studies in mice revealed that the tissue-specific glycosylation of TSH diversifies its function in the circulation to avoid crosstalk. In contrast to birds and mammals, one of the molecular machineries necessary for the seasonal reproduction of fish are localized in the saccus vasculosus from the photoreceptor to the neuroendocrine output. Thus, comparative analysis is a powerful tool to uncover the universality and diversity of fundamental properties in various organisms.
MeSH term(s)	Animals ; Circadian Rhythm/physiology ; Gonadotropin-Releasing Hormone/metabolism ; Hypothalamus/metabolism ; Photoperiod ; Pituitary Gland/metabolism ; Reproduction/physiology ; Seasons ; Signal Transduction/physiology ; Thyroid Hormones/metabolism ; Thyrotropin/metabolism ; Vertebrates/physiology
Chemical Substances	Thyroid Hormones ; Gonadotropin-Releasing Hormone (33515-09-2) ; Thyrotropin (9002-71-5)
Language	English
Publishing date	2016-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1851-x
ISSN	1095-6840 ; 0016-6480
ISSN (online)	1095-6840
ISSN	0016-6480
DOI	10.1016/j.ygcen.2015.05.009
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Article: [Animals' clever adaptation strategy for seasonal changes in environment].

Ikegami, Keisuke / Yoshimura, Takashi

Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology

2015 Volume 35, Issue 4, Page(s) 103–106

Abstract: Organisms living outside of tropical zones experience seasonal changes in environment. Organisms are using day length as a calendar to change their physiology and behavior such as seasonal breeding, hibernation, migration, and molting. A comparative ... ...

Abstract	Organisms living outside of tropical zones experience seasonal changes in environment. Organisms are using day length as a calendar to change their physiology and behavior such as seasonal breeding, hibernation, migration, and molting. A comparative biology approach revealed underlying mechanisms of vertebrate seasonal reproduction. Here we review the current understanding of vertebrate seasonal reproduction. We Aso describe the involvement of tissue-specific post-translational modification in functional diversification of a hormone.
MeSH term(s)	Adaptation, Biological/physiology ; Animals ; Birds/physiology ; Fishes/physiology ; Mammals/physiology ; Reproduction/physiology ; Seasons
Language	Japanese
Publishing date	2015-08
Publishing country	Japan
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	1285665-4
ISSN	1340-2544
ISSN	1340-2544
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Article ; Online: Circadian expression and specific localization of synaptotagmin17 in the suprachiasmatic nucleus, the master circadian oscillator in mammals.

Fujioka, Atsuko / Nagano, Mamoru / Ikegami, Keisuke / Masumoto, Koh-Hei / Yoshikawa, Tomoko / Koinuma, Satoshi / Nakahama, Ken-Ichi / Shigeyoshi, Yasufumi

Brain research

2022 Volume 1798, Page(s) 148129

Abstract: The localization and function of synaptotagmin (syt)17 in the suprachiasmatic nucleus (SCN) of the brain, which is the master circadian oscillator, were investigated. The Syt17 mRNA-containing neurons were mainly situated in the shell region while SYT17 ... ...

Abstract	The localization and function of synaptotagmin (syt)17 in the suprachiasmatic nucleus (SCN) of the brain, which is the master circadian oscillator, were investigated. The Syt17 mRNA-containing neurons were mainly situated in the shell region while SYT17 immunoreactive cell bodies and neural fibers were detected in the core and shell of the SCN and the subparaventricular zone (SPZ). Further, electron microscopy analysis revealed SYT17 in the rough endoplasmic reticulum (rER), Golgi apparatus (G), and large and small vesicles of neurons. Syt17 mRNA expression in the SCN showed a circadian rhythm, and light exposure at night suppressed its expression. In addition, the free running period of locomotor activity rhythm was shortened in Syt17-deletion mutant mice. These findings suggest that SYT17 is involved in the regulation of circadian rhythms.
MeSH term(s)	Animals ; Mice ; Circadian Rhythm/physiology ; Mammals/genetics ; Neurons/metabolism ; RNA, Messenger/metabolism ; Suprachiasmatic Nucleus/metabolism ; Synaptotagmins/metabolism
Chemical Substances	RNA, Messenger ; Synaptotagmins (134193-27-4) ; Syt17 protein, mouse
Language	English
Publishing date	2022-11-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2022.148129
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