{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:23:08Z","timestamp":1785435788660,"version":"3.56.0"},"reference-count":57,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["1R01NS110953-05"],"award-info":[{"award-number":["1R01NS110953-05"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1R01NS110953-05"],"award-info":[{"award-number":["1R01NS110953-05"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Motoneurons are under strong pressure to maintain stable motor output throughout an individual life, through homeostatic regulation of their electrical properties. Dysregulated spinal motoneuron excitability has long been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Recent work in SOD1G93A mice suggests that the homeostatic response of motoneurons becomes dysregulated as cellular processes are disrupted by the disease, causing fluctuations in motoneuron electrical properties. Yet, few studies directly test whether ALS motoneurons respond differently than wild-type motoneurons to a common chronic perturbation. Here, we used in vivo electrophysiology to test whether motoneurons from pre-symptomatic SOD1G93A mice modulate excitability differently than wild-type motoneurons in response to the same homeostatic perturbation: chronic inhibition exerted by the benzodiazepine diazepam. Using linear mixed-effects statistical models, we assessed whether diazepam treatment differentially modulated passive properties, firing behavior, spike properties, and\/or synaptic inputs in SOD1G93A versus wild-type motoneurons. We identified a significant genotype \u00d7 treatment interaction effect selectively for properties related to passive membrane integration and spike initiation, including membrane time constant, peak input resistance, and recruitment current. In contrast, firing gain, spike waveform characteristics, and synaptic inputs were largely unaffected. These findings indicate that sustained inhibitory perturbation selectively triggered overactive intrinsic compensatory mechanisms in SOD1G93A motoneurons rather than inducing widespread changes in firing or synaptic transmission. Together, our results provide direct evidence for over-active homeostatic control of motoneuron excitability and support a view of motoneuron dysfunction in ALS as a problem of altered feedback regulation rather than simply hyper- or hypo-excitability.<\/jats:p>","DOI":"10.3390\/ijms27125342","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T08:57:58Z","timestamp":1781513878000},"page":"5342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chronic Diazepam Reveals Excessive Homeostatic Gain in SOD1G93A Mouse Spinal Motoneurons"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7861-7778","authenticated-orcid":false,"given":"Emily J.","family":"Reedich","sequence":"first","affiliation":[{"name":"George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA"},{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Tzai","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Imhoff-Manuel","sequence":"additional","affiliation":[{"name":"George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA"},{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1082-0569","authenticated-orcid":false,"given":"Deyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5344-3572","authenticated-orcid":false,"given":"Marin","family":"Manuel","sequence":"additional","affiliation":[{"name":"George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA"},{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1002\/ana.21543","article-title":"Current hypotheses for the underlying biology of amyotrophic lateral sclerosis","volume":"65","author":"Rothstein","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.bbadis.2006.05.002","article-title":"The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis","volume":"1762","author":"Bogaert","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.neulet.2003.07.010","article-title":"Altered excitability of motor neurons in a transgenic mouse model of familial amyotrophic lateral sclerosis","volume":"351","author":"Pieri","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1113\/jphysiol.2004.074138","article-title":"Increased persistent Na+ current and its effect on excitability in motoneurones cultured from mutant SOD1 mice","volume":"563","author":"Kuo","year":"2005","journal-title":"J. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1152\/jn.00665.2003","article-title":"Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice","volume":"91","author":"Kuo","year":"2004","journal-title":"J. Neurophysiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10864","DOI":"10.1523\/JNEUROSCI.1340-08.2008","article-title":"Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis","volume":"28","author":"Peuscher","year":"2008","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.nbd.2013.02.011","article-title":"Embryonic alteration of motoneuronal morphology induces hyperexcitability in the mouse model of amyotrophic lateral sclerosis","volume":"54","author":"Martin","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1113\/jphysiol.2013.265843","article-title":"Adult spinal motoneurones are not hyperexcitable in a mouse model of inherited amyotrophic lateral sclerosis","volume":"592","author":"Manuel","year":"2014","journal-title":"J. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1113\/jphysiol.2010.200659","article-title":"Altered postnatal maturation of electrical properties in spinal motoneurons in a mouse model of amyotrophic lateral sclerosis","volume":"589","author":"Quinlan","year":"2011","journal-title":"J. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1113\/JP275498","article-title":"The vulnerability of spinal motoneurons and soma size plasticity in a mouse model of amyotrophic lateral sclerosis","volume":"596","author":"Dukkipati","year":"2018","journal-title":"J. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e30955","DOI":"10.7554\/eLife.30955","article-title":"Hypoexcitability precedes denervation in the large fast-contracting motor units in two unrelated mouse models of ALS","volume":"7","author":"Sharma","year":"2018","journal-title":"eLife"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1002\/stem.2354","article-title":"4-Aminopyridine Induced Activity Rescues Hypoexcitable Motor Neurons from Amyotrophic Lateral Sclerosis Patient-Derived Induced Pluripotent Stem Cells","volume":"34","author":"Naujock","year":"2016","journal-title":"Stem Cells"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.conb.2016.09.014","article-title":"Regulation of motoneuron excitability and the setting of homeostatic limits","volume":"43","author":"Giachello","year":"2017","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"O\u2019Donovan, M.J., and Falgairolle, M. (2022). Homeostatic Regulation of Motoneuron Properties in Development. Vertebrate Motoneurons, Springer International Publishing.","DOI":"10.1007\/978-3-031-07167-6"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1152\/jn.00045.2017","article-title":"PICs in motoneurons do not scale with the size of the animal: A possible mechanism for faster speed of muscle contraction in smaller species","volume":"118","author":"Huh","year":"2017","journal-title":"J. Neurophysiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1113\/JP284192","article-title":"Inhibitory interneurons show early dysfunction in a SOD1 mouse model of amyotrophic lateral sclerosis","volume":"601","author":"Cavarsan","year":"2023","journal-title":"J. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9049","DOI":"10.1038\/s41598-020-65685-8","article-title":"Excessive Homeostatic Gain in Spinal Motoneurons in a Mouse Model of Amyotrophic Lateral Sclerosis","volume":"10","author":"Kuo","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"ENEURO.0378-20.2021","DOI":"10.1523\/ENEURO.0378-20.2021","article-title":"Time Course of Alterations in Adult Spinal Motoneuron Properties in the SOD1(G93A) Mouse Model of ALS","volume":"8","author":"Huh","year":"2021","journal-title":"eNeuro"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3251","DOI":"10.1038\/s41467-021-23224-7","article-title":"Locomotor deficits in a mouse model of ALS are paralleled by loss of V1-interneuron connections onto fast motor neurons","volume":"12","author":"Allodi","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.neuropharm.2013.10.003","article-title":"Spinal inhibitory circuits and their role in motor neuron degeneration","volume":"82","author":"Tapia","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1750-3639.2010.00417.x","article-title":"Reduction in the Motoneuron Inhibitory\/Excitatory Synaptic Ratio in an Early-Symptomatic Mouse Model of Amyotrophic Lateral Sclerosis","volume":"21","author":"Sunico","year":"2010","journal-title":"Brain Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115046","DOI":"10.1016\/j.celrep.2024.115046","article-title":"Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration","volume":"43","author":"Nascimento","year":"2024","journal-title":"Cell Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e0011252026","DOI":"10.1523\/JNEUROSCI.0011-25.2026","article-title":"Motoneurons inhibitory synapses homeostatically respond to neuronal activity and modulate Amyotrophic Lateral Sclerosis pathogenesis","volume":"46","author":"Halablab","year":"2026","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Maurer, M. (2012). Dynamic Meta-Analysis as a Therapeutic Prediction Tool for Amyotrophic Lateral Sclerosis. Amyotrophic Lateral Sclerosis, InTech.","DOI":"10.5772\/1054"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Lee, A.J.B., Bi, S., Ridgeway, E., Al-Hussaini, I., Deshpande, S., Krueger, A., Khatri, A., Tsui, D., Deng, J., and Mitchell, C.S. (2025). Restoring Homeostasis: Treating Amyotrophic Lateral Sclerosis by Resolving Dynamic Regulatory Instability. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26030872"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"18595","DOI":"10.1073\/pnas.1204994109","article-title":"Benzodiazepine treatment induces subtype-specific changes in GABAA receptor trafficking and decreases synaptic inhibition","volume":"109","author":"Jacob","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1038\/s41380-026-03512-8","article-title":"Synaptic correlates of benzodiazepine tolerance","volume":"31","author":"Piot","year":"2026","journal-title":"Mol. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1038\/s41380-018-0100-y","article-title":"Diazepam-induced loss of inhibitory synapses mediated by PLC\u03b4\/Ca2+\/calcineurin signalling downstream of GABAA receptors","volume":"23","author":"Nicholson","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1523\/JNEUROSCI.17-10-03467.1997","article-title":"Silent GABAA synapses during flurazepam withdrawal are region-specific in the hippocampal formation","volume":"17","author":"Poisbeau","year":"1997","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11246","DOI":"10.1523\/JNEUROSCI.3260-09.2009","article-title":"Fast kinetics, high-frequency oscillations, and subprimary firing range in adult mouse spinal motoneurons","volume":"29","author":"Manuel","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"489470","DOI":"10.1155\/2011\/489470","article-title":"Mechanisms of GABAergic Homeostatic Plasticity","volume":"2011","author":"Wenner","year":"2011","journal-title":"Neural Plast."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"102553","DOI":"10.1016\/j.conb.2022.102553","article-title":"Homeostatic plasticity and excitation-inhibition balance: The good, the bad, and the ugly","volume":"75","author":"Chen","year":"2022","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.cell.2008.10.008","article-title":"The Self-Tuning Neuron: Synaptic Scaling of Excitatory Synapses","volume":"135","author":"Turrigiano","year":"2008","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Pierrot-Deseilligny, E., and Burke, D. (2012). The Circuitry of the Human Spinal Cord, Cambridge University Press.","DOI":"10.1017\/CBO9781139026727"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1113\/jphysiol.1972.sp009818","article-title":"Synaptic actions of single interneurones mediating reciprocal Ia inhibition of motoneurones","volume":"222","author":"Jankowska","year":"1972","journal-title":"J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1113\/jphysiol.1971.sp009488","article-title":"Recurrent inhibition of interneurones monosynaptically activated from group Ia afferents","volume":"215","author":"Hultborn","year":"1971","journal-title":"J. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bhumbra, G.S., and Beato, M. (2018). Recurrent excitation between motoneurones propagates across segments and is purely glutamatergic. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2003586"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Pfaff, D.W. (2013). Spinal Interneurons. Neuroscience in the 21st Century, Springer.","DOI":"10.1007\/978-1-4614-1997-6"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.brainresrev.2007.06.022","article-title":"Spinal interneuronal networks in the cat: Elementary components","volume":"57","author":"Jankowska","year":"2008","journal-title":"Brain Res. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.expneurol.2019.04.017","article-title":"Dysregulation of mechanosensory circuits coordinating the actions of antagonist motor pools following peripheral nerve injury and muscle reinnervation","volume":"318","author":"Horstman","year":"2019","journal-title":"Exp. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/BF00180822","article-title":"The pharmacokinetics of diazepam and desmethyldiazepam in rat brain and plasma","volume":"88","author":"Friedman","year":"1986","journal-title":"Psychopharmacology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1038\/sj.npp.1300800","article-title":"Differential effects of two chronic diazepam treatment regimes on withdrawal anxiety and AMPA receptor characteristics","volume":"31","author":"Allison","year":"2006","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1016\/S0022-3565(25)10157-2","article-title":"Long-term treatment with abecarnil does not induce diazepam-like dependence in mice","volume":"264","author":"Steppuhn","year":"1993","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1152\/jn.00714.2011","article-title":"Effect of prolonged riluzole exposure on cultured motoneurons in a mouse model of ALS","volume":"107","author":"Schuster","year":"2012","journal-title":"J. Neurophysiol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Mahrous, A.A., Heit, B.S., and Heckman, C.J. (2026). Riluzole treatment paradoxically increases motoneuron excitability in ALS due to hyperactive homeostasis. bioRxiv.","DOI":"10.64898\/2026.03.23.713695"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"102905","DOI":"10.1016\/j.pneurobio.2026.102905","article-title":"Spinal motoneuron excitability is homeostatically regulated through \u03b2-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice","volume":"260","author":"Antonucci","year":"2026","journal-title":"Prog. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Manuel, M., and Heckman, C.J. (2012). Simultaneous intracellular recording of a lumbar motoneuron and the force produced by its motor unit in the adult mouse in vivo. J. Vis. Exp. JoVE, e4312.","DOI":"10.3791\/4312"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3984","DOI":"10.1113\/JP290593","article-title":"Machine-learning classification of motor unit types in the adult mouse","volume":"604","author":"Ahorklo","year":"2026","journal-title":"J. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"ENEURO.0461-20.2020","DOI":"10.1523\/ENEURO.0461-20.2020","article-title":"Sub-optimal Discontinuous Current-Clamp switching rates lead to deceptive mouse neuronal firing","volume":"8","author":"Manuel","year":"2021","journal-title":"eNeuro"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/0006-8993(95)00077-4","article-title":"Experimental analysis of the method of \u2018peeling\u2019 exponentials for measuring passive electrical properties of mammalian motoneurons","volume":"675","author":"Engelhardt","year":"1995","journal-title":"Brain Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1109\/TBME.2004.827531","article-title":"Estimating action potential thresholds from neuronal time-series: New metrics and evaluation of methodologies","volume":"51","author":"Sekerli","year":"2004","journal-title":"IEEE Trans. Biomed. Eng."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/s41586-020-2649-2","article-title":"Array programming with NumPy","volume":"585","author":"Harris","year":"2020","journal-title":"Nature"},{"key":"ref_53","first-page":"1","article-title":"pandas: A foundational Python library for data analysis and statistics","volume":"14","author":"McKinney","year":"2011","journal-title":"Python High Perform. Sci. Comput."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.21105\/joss.03021","article-title":"seaborn: Statistical data visualization","volume":"6","author":"Waskom","year":"2021","journal-title":"J. Open Source Softw."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: A 2D Graphics Environment","volume":"9","author":"Hunter","year":"2007","journal-title":"Comput. Sci. Eng."},{"key":"ref_56","unstructured":"Seabold, S., and Perktold, J. (July, January 28). statsmodels: Econometric and statistical modeling with python. Proceedings of the 9th Python in Science Conference, Austin, TX, USA."},{"key":"ref_57","first-page":"1","article-title":"brms: An R Package for Bayesian Multilevel Models Using Stan","volume":"80","year":"2017","journal-title":"J. Stat. Softw."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5342\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:23:30Z","timestamp":1781843010000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,13]]},"references-count":57,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125342"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125342","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,13]]}}}