
==== Front
Pain Rep
Pain Rep
PAIREP
Painreports
Pain Reports
2471-2531
Wolters Kluwer Philadelphia, PA

PAINREPORTS-D-24-0020
10.1097/PR9.0000000000001186
00010
3
2
Basic Science
Research Paper
Modulation of mechanosensation by endogenous dopaminergic signaling in the lateral parabrachial nucleus in mice
Koo Ho kooho@utmb.edu

Wang Jigong jigwang@utmb.edu

Pariyar Ramesh rapariya@UTMB.EDU

Hammond Regan M. rmhammon@UTMB.EDU

https://orcid.org/0000-0003-4306-0305
La Jun-Ho
Department of Neurobiology, University of Texas Medical Branch, Galveston, TX, USA
Corresponding author. Address: Department of Neurobiology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555. Tel.: +1 (409) 772-6549; fax: +1 (409) 772-3381. E-mail address: jula@utmb.edu (J.-H. La).
10 2024
10 9 2024
9 5 e118608 2 2024
09 5 2024
18 6 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Noxious mechanical stimulation releases dopamine in the lateral parabrachial nucleus. This endogenous dopamine signaling decreases and increases mechanosensitivity through D1- and D2-like receptors, respectively.

Abstract

Introduction:

The lateral parabrachial nucleus (LPBN), a crucial hub for integrating and modulating diverse sensory information, is known to express both D1 and D2 dopamine receptors and receive dopaminergic inputs. However, the role of the LPBN's dopaminergic system in somatosensory processing remains largely unexplored. In this study, we investigated whether mechanical sensory stimulation triggers dopamine release in the LPBN and how D1- and D2-like receptor signaling in the LPBN influences mechanosensitivity in mice.

Methods:

We used a G-protein-coupled receptor–based dopamine sensor to monitor dopamine release in the LPBN and a von Frey filament assay to measure the mechanical threshold for nocifensive withdrawal in mouse hind paws after unilateral microinjection of D1- or D2-like receptor antagonist into the LPBN.

Results:

Noxious mechanical stimulation increased the dopamine sensor signal in the LPBN. Thresholds of nocifensive withdrawal from mechanical stimulation were decreased by the D1-like receptor antagonist SCH-23390 (0.1 µg) but increased by the D2-like receptor antagonist eticlopride (1 µg). In the intraplantar capsaicin injection model that develops mechanical hypersensitivity in the injected paw, the dopamine sensor signal in the LPBN was increased, and eticlopride (1 µg) in the LPBN significantly inhibited the capsaicin-induced mechanical hypersensitivity.

Conclusions:

These results suggest that endogenous dopaminergic signaling occurs in the LPBN upon noxious mechanical stimulation, inhibiting mechanosensitivity through D1-like receptors while enhancing it through D2-like receptors. D2-like receptor signaling in the LPBN may contribute to an injury-induced increase in mechanical nociception, indicating that inhibiting the receptor within the LPBN could offer potential as a novel analgesic strategy.

Keywords:

Lateral parabrachial nucleus
Dopamine
Dopamine receptors
Somatosensation
Mechanosensitivity
National Institute of Neurological Disorders and StrokeR01 NS112344 Jun-Ho LaOPEN-ACCESSTRUE
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pmc1. Introduction

Pain and sensory modulation in mammals involves complex neural circuits, with the lateral parabrachial nucleus (LPBN) playing a pivotal role. The LPBN serves as a crucial relay and modulatory station for various sensory inputs, integrating and processing information that is vital for appropriate physiological and behavioral responses.2,9,25,35 Notably, the LPBN is known to receive inputs from the brain areas where dopaminergic neurons reside, such as the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNpc).11,31,32 Immunohistochemistry, in situ hybridization, and transcriptomic profiling revealed clusters of PBN neurons expressing dopamine receptors D1 and D2 subtypes.5,21,26 Collectively, these findings suggest a significant role for dopamine in modulating sensory information within this nucleus.

Dopamine, a key neurotransmitter in the brain, is extensively involved in regulating motor functions, reward mechanisms, and pain perception.3,33,34 The influence of the dopaminergic system on pain and sensory processing has been a subject of increasing interest, particularly in understanding the mechanisms underlying various pain conditions and developing effective pain management strategies. Although the role of dopamine in brain regions such as the basal ganglia and spinal cord has been well characterized, its function in the LPBN, especially regarding somatosensory modulation, is not well understood; to date, the only published study on dopamine signaling in the LPBN is related to its role in food intake regulation.14

This gap in knowledge presents a critical area of investigation because understanding the dopaminergic modulation in the LPBN could offer new insights into the neural mechanisms of sensory processing and pain perception. Therefore, this study aimed to elucidate the role of endogenous dopaminergic signaling in the LPBN using a murine model. Specifically, we examined how the LPBN dopaminergic system responds to mechanical stimulation and whether this system modulates mechanical sensory responses in mice. Using the G-protein-coupled receptor–based fluorescent dopamine sensor GRABDA, we detected dopamine levels in the LPBN. We also used pharmacological approaches—microinjection of the D1-like receptor antagonist SCH-23390 and the D2-like receptor antagonist eticlopride into the LPBN—to unveil the specific contributions of endogenous D1- and D2-like receptor signaling to mechanosensory processing in the LPBN at a behavioral level. Portions of the data have been presented in abstract form.17

2. Materials and methods

2.1. Animals

C57BL/6N mice, aged 9 to 12 weeks and of both sexes, were either bred in our facility or obtained from Charles River (Houston, TX). The mice were kept in groups of up to 5 mice per cage, under a 12-hour light–12-hour dark cycle, and provided with unlimited food and water. All experimental procedures were conducted in compliance with the guidelines set by the National Institute of Health and were approved by the Institutional Animal Care and Use Committee of the University of Texas Medical Branch.

2.2. Mechanosensitivity tests

Mice were mechanically stimulated on the central region of the plantar side of their hind paw with von Frey filaments (VFF). Nocifensive paw withdrawal thresholds (PWT) were longitudinally measured over time (before and after drug treatment); the simplified up-down (SUDO) method was used to detect PWT in gram force.4 Rapid paw withdrawal, biting, shaking, and licking of the paw during or immediately after the stimulus were regarded as a positive nocifensive response.

2.3. Intraplantar capsaicin injection

To induce mechanical hypersensitivity, freshly prepared capsaicin solution (0.1% in 10% ethanol, 10% Tween-20, and 80% saline; Sigma-Aldrich, St. Louis, MO) was intradermally injected (5 μL) into the base of the third and fourth toes of the right plantar hind paw. Anesthesia with 2.0 to 2.5% isoflurane was maintained throughout the injection procedure.

2.4. Surgical procedures

Mice were anesthetized with isoflurane (3% for induction and 1.5∼2% for maintenance) and mounted in a stereotaxic frame. The skull was exposed by a midline incision on the scalp. Subsequently, a burr hole was meticulously drilled to access the LPBN (AP: 5.2 mm; ML: 1.25 mm; and DV: 3.4 mm) located in the right hemisphere for drug administration through a cannula or bilaterally for fiber photometry.

2.5. Drug administration through an intracranial cannula

A 26-gauge guide cannula (RWD Life Science Inc., Sugar Land, TX) was implanted into the right-side LPBN. The cannula was fixed with dental cement and sealed with a dummy cannula. After a recovery period of 7 days, a microinjection into the PBN was made using a stainless-steel injector (30 gauge; RWD Life Science Inc.) connected to polyethylene tubing. This tubing was then attached to a 10-μL Hamilton syringe, which was subsequently mounted onto an infusion pump (Legato 130, Kd Scientific, Holliston, MA); 0.08-μL microinjections were delivered at a rate of 0.1 μL/min. The injector remained in place for an additional 2 minutes after infusion to allow for sufficient diffusion. All infusions were performed approximately 30 minutes before behavioral testing.

2.6. Drugs and dosages

SCH-23390 (D1-like receptor antagonist) (Tocris Bioscience, Bristol, United Kingdom) and eticlopride (D2-like receptor antagonist) (Sigma-Aldrich) were dissolved in sterile 0.9% saline solutions at varying concentrations. The doses for SCH-23390 were 0.01, 0.05, 0.1, and 0.5 µg per 0.1 µL, and for eticlopride, doses were 0.1, 0.3, and 1 µg per 0.1 µL.

2.7. Fiber photometry

AAV9-hSyn-GRABDA2h (2.5 × 1013 vg/mL, 150 nL; a gift from Dr. Yulong Li, Addgene 140554-AAV9, Watertown, MA) was bilaterally administered into the LPBN. Three weeks after injection, optical fibers (400-µm outer diameter, 0.5 numerical aperture; RWD Life Science Inc.) were bilaterally implanted into the LPBN and fixed with dental cement. The mice were then allowed a recovery period of 7 days, after which we recorded photometry signals from awake or anesthetized mice using the R-810 fiber photometry system (RWD Life Science Inc). The fluorescent signal was normalized by the standard z-score calculation method: Z-score = (x – mean)/SD, in which x is the ΔF/F of the perievent, mean is the mean of the baseline time window, and SD is the standard deviation of the baseline time window. The signals from both sides of LPBN were combined (recordings after tail stimulation in awake mice) or separately analyzed (recordings after paw stimulation in anesthetized mice).

2.8. Data analysis

We initially conducted preliminary experiments using 3 to 4 mice per group and estimated animal numbers per group for ≥80% statistical power at α = 0.05 using lme4 and simr packages based on the preliminary results. For statistical comparisons, PWT (in gram force) was first log-transformed,23 and then, the difference from the baseline logPWT (ΔlogPWT) was calculated for each time point. The ΔlogPWTs of drug-treated groups were compared with those of the control group using linear mixed model analysis (with the AR1 covariance matrix for repeated measures and random intercepts for the subject variance) followed by Sidak multiple comparison tests at each time point (SPSS ver. 28, IBM, Armonk, NY). To construct a dose–response curve, the area under the ΔlogPWT-Time curve (AUC) was calculated from each mouse's data. For each antagonist, 4 dose–response curves [for the ipsilateral and contralateral paws of males and females (2 sides × 2 sexes)] were analyzed together to assess any effects of antagonist dose, sex, side, and their interactions on the dose–response profile using a linear mixed model with ipsilateral and contralateral sides as a repeated variable and random intercepts for the subject variance. The degrees of freedom were adjusted by the Satterthwaite method. Sidak multiple comparison tests were used for multiple comparison tests. Values are presented as mean ± SEM with n, the number of mice.

3. Results

3.1. Dopamine is released in the lateral parabrachial nucleus in response to noxious mechanical stimulation

To investigate whether dopamine levels change in the LPBN in response to mechanical stimulation, we virally delivered GRABDA2h into both sides of the LPBN of mice and monitored the fluorescent signal using fiber photometry in awake, freely moving mice while applying either a tail pinch or tail touch/stroking stimulus (Fig. 1A). Application of a tail pinch resulted in a robust increase in the signal when compared with tail stroking (Fig. 1B). Systemic administration of a D2-like receptor antagonist (eticlopride 1 mg/kg, intraperitoneal), which inhibits dopamine binding to GRABDA,29 significantly reduced this tail pinch-evoked elevation of GRABDA signal in the LPBN (Fig. 1C).

Figure 1. Noxious mechanical stimulation increases dopamine release in the lateral parabrachial nucleus (LPBN) in awake mice. (A) Dopamine biosensor (GRABDA2h) was expressed in the LPBN through viral vectors, and optic fibers were implanted in the LBPN. Although awake, these mice were mechanically stimulated with a tail pinch (noxious) or tail touch/stroking (innocuous) stimulus, and the dopamine levels in the LPBN were measured using fiber photometry. (B) The GRABDA2h fluorescent signal was robustly increased in the LPBN in response to tail pinch compared to tail touch (n = 5). (C) A D2-like receptor antagonist (eticlopride 1 mg/kg, i.p.) blunted the tail pinch-evoked signal increase (n = 2). The dotted line and shaded area in the plots indicate the stimulation initiation and duration.

The LPBN bilaterally receives sensory inputs from the dorsal horn projection neurons,10,12 suggesting that noxious mechanical stimulation of either side of the body will increase dopamine release in the nucleus. For reliable stimulation of hind paws during fiber photometry, we anesthetized mice and applied pinching, brushing, and von Frey filament probing to each hind paw. As shown in Figure 2, an increase in GRABDA signals in the LPBN was observed when either hind paw was stimulated with pinch and stiff von Frey filaments. The signal increase was more pronounced when the hind paw contralateral to the recording side was stimulated.

Figure 2. Dopamine is released in the lateral parabrachial nucleus (LPBN) upon mechanical stimulation of either side of the paw in anesthetized mice. Mice were under anesthesia for reliable fiber photometry during hind paw stimulation. GRABDA2h signals were recorded from LPBN on one side while stimulating each hind paw. (A) Pinching, but not brushing, the paw increased the dopamine sensor signals in the LPBN. Note that the signal increase was more pronounced when the contralateral paw was stimulated (n = 3). (B) Probing the paw with stiff von Frey filaments also increased the dopamine sensor signals in the LPBN (n = 3). The dotted line and shaded area in the plots indicate the stimulation initiation and duration.

3.2. D1-like receptor antagonism in the lateral parabrachial nucleus heightens mechanosensitivity

To investigate the role of LPBN dopaminergic signaling through D1-like receptors in mechanosensation, we stimulated both hind paws with von Frey filaments before and after unilateral microinjection of SCH-23390 (0.01–0.5 µg), a D1-like receptor antagonist, into the right-side LPBN and measured the thresholds for nocifensive withdrawal. The dose range was chosen based on the literature showing the effect of this antagonist on various behaviors after intracranial injection.6,13,28

In males (n = 5–6/dose, Fig. 3A–C), the antagonist treatment showed a trend toward decreased withdrawal thresholds (ie, increased mechanosensitivity) at the dose of 0.1 µg. In females (n = 6–7/dose, Fig. 3D–F), the decrease in mechanical thresholds at 0.1 µg was statistically significant. A higher dose (0.5 µg) did not follow this trend, resulting in a V-shape dose–response curve (Fig. 3C). When all 4 dose–response curves (Fig. 3C, F; the figures were separated by sex for visual clarity) were analyzed together to assess any effects of antagonist dose, sex, side, and their interactions on the dose–response profile, only the antagonist dose (F(4,50) = 6.173, P < 0.001) was found to have a significant effect on the profile. Subsequent Sidak multiple comparison tests revealed that overall, the antagonist at 0.1 µg significantly decreased hind paw mechanical thresholds from baseline levels (t(50) = 3.518, P = 0.004).

Figure 3. Dopamine in the lateral parabrachial nucleus (LPBN) decreases mechanosensitivity through D1-like receptors. Paw withdrawal thresholds (PWT) were measured using von Frey filaments before and after microinjecting SCH-23390, a D1-like receptor antagonist, into the right-side PBN. (A-C) In males (n = 5–6/dose), the antagonist at a 0.1-µg dose showed a trend toward decreased mechanical thresholds (0.1 µg). (D-F) In females (n = 6–7/dose), the antagonist at a 0.1-µg dose significantly decreased mechanical thresholds in both hind paws ipsilateral and contralateral to the antagonist injection side. In both sexes, a higher dose (0.5 µg) did not produce such an effect, yielding a V-shape dose–response curve (C and F). *P < 0.05 and **P < 0.01 vs saline (vehicle) at a given time point by post hoc Sidak test followed by linear mixed model analysis.

3.3. D2-like receptor antagonism in the lateral parabrachial nucleus suppresses mechanosensitivity

We next investigated the role of LPBN dopaminergic signaling through D2-like receptors in mechanosensation by microinjecting their antagonist eticlopride (0.1–1 µg based on the literature6,13,28) in the right-side LPBN and measuring the thresholds of nocifensive withdrawal from von Frey filament stimulation. In both male (n = 5–7/dose) and female (n = 4–6/dose) mice, the D2-like receptor antagonist at 1 µg significantly increased withdrawal thresholds (ie, reduced mechanosensitivity) in both ipsilateral and contralateral hind paws (Fig. 4). When all 4 dose–response curves (Fig. 4C, F; the figures were separated by sex for visual clarity) were analyzed together to assess any effects of antagonist dose, sex, side, and their interactions on the dose–response profile, we detected significant main effects of the antagonist dose (F(3,37) = 14.569, P < 0.001; a significant antagonist effect at 1 µg [t(37) = 5.656, P < 0.001 by Sidak test]), side (F(1,37) = 7.951, P = 0.008; overall greater antagonist effects in the ipsilateral than in the contralateral hind paw), sex (F(1,37) = 6.501, P = 0.015), and the interaction between side and sex (F(1,37) = 5.485, P = 0.025; a greater antagonist effect in the ipsilateral than in the contralateral hind paw only in males [t(37) = 3.702, P = 0.001 by Sidak test]).

Figure 4. Dopamine in the lateral parabrachial nucleus (LPBN) increases mechanosensitivity through D2-like receptors. Paw withdrawal thresholds (PWT) were measured using von Frey filaments before and after microinjecting eticlopride, a D2-like receptor antagonist, into the right-side PBN. In both males (A-C, n = 5–7/dose) and females (D-F, n = 4–6/dose), the D2-like receptor antagonist (1 µg) significantly increased mechanical thresholds in hind paws. In males, the effect was more pronounced in the ipsilateral than in the contralateral paw. *P < 0.05 and **P < 0.01 vs saline (vehicle) at a given time point by post hoc Sidak test followed by linear mixed model analysis in (A, B, D, and E); **P < 0.01 between contra and ipsi in (C).

3.4. D2-like receptor antagonism in the lateral parabrachial nucleus alleviates mechanical hypersensitivity

The above results suggest that blocking the D2-like receptor in the LPBN may have a therapeutic effect on mechanical pain. To test this possibility, we used the intraplantar capsaicin injection model, which develops robust mechanical hypersensitivity outside the injection area (Fig. 5A).19,20 Under anesthesia, we found that intraplantar capsaicin injection significantly increased GRABDA signals in the ipsilateral LPBN (Fig. 5B). In this capsaicin model, the administration of eticlopride (1 μg), a D2-like receptor antagonist, into the ipsilateral LPBN significantly reduced mechanical hypersensitivity in the capsaicin-injected hind paw in both sexes (n = 4 each; Fig. 5C).

Figure 5. D2-like receptor antagonism in the lateral parabrachial nucleus (LPBN) alleviates capsaicin-induced mechanical hypersensitivity. (A) Capsaicin was injected at the base of the toes on the plantar side, and von Frey filaments (VFF) were applied for mechanical stimulation to the center of the capsaicin-injected paw. (B) Under anesthesia, intraplantar capsaicin (Cap) injection (red arrow) increased the dopamine biosensor signals in the ipsilateral LPBN (n = 5). (C) D2-like receptor antagonist (eticlopride 1 µg), microinjected into the LPBN ipsilateral to the capsaicin-injected paw, temporarily restored the decreased mechanical thresholds in the paw in both males (n = 4) and females (n = 4). *P < 0.05 and **P < 0.01 vs saline (vehicle) at a given time point by post hoc Sidak test followed by linear mixed model analysis.

4. Discussion

This study provides evidence for the dimorphic role of LPBN dopaminergic signaling in modulating mechanosensory processing. Our findings demonstrate that the activation of dopaminergic signaling within the LPBN, induced by mechanical stimulation, has opposing effects on mechanosensitivity depending on the targeted receptor subtype. Specifically, signaling through the D1-like receptor suppresses mechanosensitivity (as evidenced by the decreased mechanical thresholds with its antagonist SCH-23390 at 0.1 μg). By contrast, signaling through the D2-like receptor in the LPBN heightens mechanosensitivity (as evidenced by the increased mechanical thresholds with its antagonist eticlopride at 1 μg). The ability of eticlopride (1 μg) to attenuate capsaicin-induced mechanical hypersensitivity further supports the critical role of this receptor signaling within the LPBN in increasing mechanosensitivity.

Interestingly, a higher dose (0.5 μg) of the D1-like receptor antagonist showed no effect on mechanical thresholds, suggesting that the antagonist might be nonspecific/toxic18,22 at this dose within the LPBN, or signaling through D1-like receptors of relatively low-binding probability/affinity to the antagonist (which will require a high concentration of the antagonist for inhibition) might counteract the effect of its high-affinity counterpart in the LPBN. In this regard, although the range of high doses is not identical across studies, SCH-23390 has often shown diminished antagonist effects upon dose escalation.13,16,24,27

Statistical comparisons of D2-like receptor antagonist dose–response curves indicated a sex difference in terms of the effect of the antagonist on mechanosensitivity between the ipsilateral and contralateral hind paws. Specifically, only in males, the inhibitory effect of eticlopride on mechanosensitivity was greater in the ipsilateral than in the contralateral paws. It is noteworthy that noxious mechanical stimulation of the ipsilateral paw tended to increase the GRABDA signals in the LPBN less than that of the contralateral paw (Fig. 2), suggesting that dopaminergic signaling by/for the ipsilateral mechanical nociception may be more easily suppressed at a given dose of dopamine receptor antagonist. This could be the reason for the greater effect of eticlopride on the ipsilateral paw mechanosensitivity. The results that this ipsilateral vs contralateral difference was statistically significant only in males for the D2 receptor antagonist warrant further studies investigating potential sex differences in the expression levels/patterns of D2- vs D1-like receptors in the LPBN.

Previously, dopamine was shown to “suppress” glutamatergic synaptic transmission in the PBN through a presynaptic mechanism without the involvement of intermediaries such as GABAB and adenosine receptors arising from postsynaptic and presynaptic sides. Activation of D1-like receptors primarily mediates this suppressive effect on glutamatergic synaptic response in the PBN.7 Considering the importance of LPBN glutamatergic neuronal activity in mechanical nociception,30 these previous findings align with our present results, showing that antagonism of D1-like receptors in the LPBN increases mechanosensitivity (Fig. 2) because blocking these receptors is expected to increase glutamatergic synaptic transmission in the LPBN (by inhibition of suppression). However, our findings deviate from the previous studies regarding the role of D2-like receptor signaling in mechanosensation. Specifically, although Chen et al.7 found a minor contribution of the D2-like receptor to the dopamine-induced suppression of glutamatergic synaptic transmission in the PBN, we found an opposing effect of D2-like receptor signaling in the LPBN compared with that of D1-like receptor signaling on mechanosensitivity (Fig. 3 vs Fig. 4). The reason for this discrepancy is currently unknown, but some differences such as species (mouse vs rats) and experimental settings (in vivo vs ex vivo) between the present and previous studies are noteworthy.

It is widely recognized that dopamine receptors interact with various signaling pathways.15 Primarily, D1-like receptors activate adenylyl cyclase through the Gs protein, whereas D2-like receptors inhibit adenylyl cyclase through the Gi protein. Although D2-like receptors also play a role in inhibiting calcium channels, they can induce neuronal membrane depolarization by activating nonselective cationic conductance, a process involving phospholipase C (PLC) stimulation without an increase in intracellular calcium.1 This stimulatory/excitatory action of D2-like receptor signaling might explain our results showing that the receptor in the LPBN heightens mechanosensitivity. However, it is noteworthy that neither the G protein nor the PLC pathway was involved in the dopamine-induced suppression of glutamatergic synaptic responses in the PBN.8 Further studies are needed to delineate the specific signaling pathways through which D1- and D2-like receptors modulate somatosensory processing in the LPBN.

We acknowledge some limitations in this study. First, the dosage range and the unilateral microinjection approach in this study may not fully capture the spectrum of dopamine's role in mechanosensitivity modulation in the LPBN. Second, the role of LPBN dopaminergic signaling in processing other somatosensory modalities (eg, heat, cold, and itch) remains to be elucidated. Third, although neurons in the VTA and SNpc project to the PBN,12,32,35 it is essential to identify precise brain regions providing dopaminergic inputs to the LPBN for somatosensory modulation.

In conclusion, endogenous dopaminergic signaling in the LPBN suppresses and enhances mechanosensitivity through D1- and D2-like receptors, respectively. D2-like receptors seem to contribute to injury-induced mechanical hypersensitivity. Therefore, specific inhibition of D2 receptor-mediated dopaminergic signaling in the LPBN may hold analgesic potential.

Disclosures

The authors have no conflict of interest to declare.

Acknowledgments

This study was supported by NIH R01 NS112344 (J.H.L.).

Data availability: The data are available upon request to the corresponding author J.H.L.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
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