{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T10:01:37Z","timestamp":1785492097064,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,29]]},"group-title":"Neuroscience","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"crossref","award":["23AARG-NTF-1029524"],"award-info":[{"award-number":["23AARG-NTF-1029524"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH\/GMS","award":["1R35GM145319-01"],"award-info":[{"award-number":["1R35GM145319-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Alzheimer\u2019s disease (AD) is characterized by progressive functional neuronal decline ultimately resulting in severe cognitive impairment. However, how neuron function is altered at the cellular level during the critical early stages of the disease and how disease progression relates to the process of normal neuronal aging are poorly understood. To address these fundamental questions, we performed comprehensive multi-neuron imaging in\n                  <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                  (\n                  <jats:italic>C. elegans<\/jats:italic>\n                  ) with pan-neuronal expression of human amyloid \u03b2\n                  <jats:sub>1-42<\/jats:sub>\n                  peptide (nA\u03b2), the major plaque forming peptide in early AD progression. Measuring neuron activity, connectivity and system wide dynamics with single cell resolution across the\n                  <jats:italic>C. elegans<\/jats:italic>\n                  lifespan, we compare A\u03b2-associated neuronal dysfunction with that of normal aging. Our experiments revealed that nA\u03b2 expressing animals exhibit a unique loss of positively correlated neuron connectivity, premature disruption of system wide dynamics, and reduced overall neuronal activity. These neuronal effects correspond to premature impairments in behavior including mechanosensory response as well as the animal\u2019s ability to navigate its environment (\n                  <jats:italic>i.e<\/jats:italic>\n                  ., chemotaxis and thermotaxis). The effects of nA\u03b2 expression are distinct from, and in addition to, the process of normal aging that is characterized by a progressive loss of anti-correlated (\n                  <jats:italic>i.e.<\/jats:italic>\n                  inhibitory) neuronal signaling and slower behavioral decline. An increase in resistance to aldicarb, an acetylcholinesterase inhibitor, as well as downregulation of key one-carbon metabolism (OCM) genes (\n                  <jats:italic>metr-1, sams-1<\/jats:italic>\n                  , involved in choline metabolism, the precursor of acetylcholine synthesis) implicate compromised acetylcholine-mediated excitatory transmission in nA\u03b2 expressing worms. Supplementation with OCM metabolites (choline, methionine, cysteine) in nA\u03b2 expressing worms improved behavior and helped restore OCM gene expression as well as levels of Ach signaling. Likewise, perturbation of the serine synthesis pathway (SSP) that links glycolysis to OCM, altered Ach signaling and OCM gene expression in nA\u03b2 animals. Genetic mutations that directly regulate excitatory\/inhibitory balance neuronal signaling (\n                  <jats:italic>unc-2<\/jats:italic>\n                  \/CaV2\u03b1) also help to reduce nA\u03b2-associated behavioral deficits, while NMDA receptor (\n                  <jats:italic>nmr-1<\/jats:italic>\n                  ) mutants showed neither protective effect nor it directly rescue the loss of positive neuron correlativity unique to nA\u03b2 animals. Our results demonstrate the unique effects of nA\u03b2 toxicity on neuronal dynamics and connectivity as well as the role of key metabolic pathways within the context of a complete, intact, aging nervous system.\n                <\/jats:p>","DOI":"10.64898\/2026.07.27.740981","type":"posted-content","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:35:13Z","timestamp":1785324913000},"source":"Crossref","is-referenced-by-count":0,"title":["Early Amyloid-\u03b2 Toxicity Disrupts Nervous System Connectivity During Aging in\n                  <i>Caenorhabditis elegans<\/i>"],"prefix":"10.64898","author":[{"given":"Dilip Kumar","family":"Yadav","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Physiology and Biophysics, Chobanian & Avedisian School of Medicine, Boston University School of Medicine, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher W","family":"Connor","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology and Biophysics, Chobanian & Avedisian School of Medicine, Boston University School of Medicine, United States"},{"name":"Department of Anesthesiology, Massachusetts General Brigham, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2763-3938","authenticated-orcid":false,"given":"Christopher V","family":"Gabel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology and Biophysics, Chobanian & Avedisian School of Medicine, Boston University School of Medicine, United States"},{"name":"Neurophotonics Center, Boston University, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026073102551235000_2026.07.27.740981v1.1","doi-asserted-by":"crossref","unstructured":"Holtzman DM , Morris JC , Goate AM . Alzheimer\u2019s disease: The challenge of the second century. Vol. 3, Science Translational Medicine. 2011.","DOI":"10.1126\/scitranslmed.3002369"},{"key":"2026073102551235000_2026.07.27.740981v1.2","doi-asserted-by":"crossref","unstructured":"Shankar GM , Walsh DM . Alzheimer\u2019s disease: Synaptic dysfunction and A\u03b2. Mol Neurodegener. 2009;4(1).","DOI":"10.1186\/1750-1326-4-48"},{"key":"2026073102551235000_2026.07.27.740981v1.3","doi-asserted-by":"crossref","unstructured":"Frere S , Slutsky I . Alzheimer\u2019s Disease: From Firing Instability to Homeostasis Network Collapse. Vol. 97, Neuron. 2018.","DOI":"10.1016\/j.neuron.2017.11.028"},{"key":"2026073102551235000_2026.07.27.740981v1.4","doi-asserted-by":"crossref","unstructured":"Liu Y , Tan Y , Zhang Z , Yi M , Zhu L , Peng W . The interaction between ageing and Alzheimer\u2019s disease: insights from the hallmarks of ageing. Vol. 13, Translational Neurodegeneration. 2024.","DOI":"10.1186\/s40035-024-00397-x"},{"key":"2026073102551235000_2026.07.27.740981v1.5","doi-asserted-by":"crossref","unstructured":"Pena F , Gutierrez-Lerma A , Quiroz-Baez R , Arias C . The Role of beta-Amyloid Protein in Synaptic Function: Implications for Alzheimers Disease Therapy. Curr Neuropharmacol. 2006;4(2).","DOI":"10.2174\/157015906776359531"},{"key":"2026073102551235000_2026.07.27.740981v1.6","doi-asserted-by":"crossref","unstructured":"Mucke L , Selkoe DJ . Neurotoxicity of amyloid \u03b2-protein: Synaptic and network dysfunction. Cold Spring Harb Perspect Med. 2012;2(7).","DOI":"10.1101\/cshperspect.a006338"},{"key":"2026073102551235000_2026.07.27.740981v1.7","doi-asserted-by":"crossref","unstructured":"Guo T , Zhang D , Zeng Y , Huang TY , Xu H , Zhao Y . Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer\u2019s disease. Vol. 15, Molecular Neurodegeneration. 2020.","DOI":"10.1186\/s13024-020-00391-7"},{"key":"2026073102551235000_2026.07.27.740981v1.8","doi-asserted-by":"crossref","unstructured":"Coup\u00e9 P , Manj\u00f3n JV , Lanuza E , Catheline G . Lifespan Changes of the Human Brain In Alzheimer\u2019s Disease. Sci Rep. 2019;9(1).","DOI":"10.1038\/s41598-019-39809-8"},{"key":"2026073102551235000_2026.07.27.740981v1.9","doi-asserted-by":"crossref","unstructured":"Roussos A , Kitopoulou K , Borbolis F , Palikaras K . Caenorhabditis elegans as a Model System to Study Human Neurodegenerative Disorders. Vol. 13, Biomolecules. 2023.","DOI":"10.3390\/biom13030478"},{"key":"2026073102551235000_2026.07.27.740981v1.10","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000003304"},{"key":"2026073102551235000_2026.07.27.740981v1.11","doi-asserted-by":"crossref","unstructured":"Wirak GS , Florman J , Alkema MJ , Connor CW , Gabel C V . Age-associated changes to neuronal dynamics involve a disruption of excitatory\/inhibitory balance in C. elegans. Elife. 2022;11.","DOI":"10.7554\/eLife.72135"},{"key":"2026073102551235000_2026.07.27.740981v1.12","doi-asserted-by":"crossref","unstructured":"Maest\u00fa F , de Haan W , Busche MA , DeFelipe J . Neuronal excitation\/inhibition imbalance: core element of a translational perspective on Alzheimer pathophysiology. Vol. 69, Ageing Research Reviews. 2021.","DOI":"10.1016\/j.arr.2021.101372"},{"key":"2026073102551235000_2026.07.27.740981v1.13","doi-asserted-by":"crossref","unstructured":"Teo E , Ravi S , Barardo D , Kim HS , Fong S , Gassiot AC , et al. Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta. Elife. 2019;8.","DOI":"10.7554\/eLife.50069"},{"key":"2026073102551235000_2026.07.27.740981v1.14","doi-asserted-by":"crossref","unstructured":"Wu Y , Wu Z , Butko P , Christen Y , Lambert MP , Klein WL , et al. Amyloid-\u03b2-induced pathological behaviors are suppressed by Ginkgo biloba extract EGB 761 and ginkgolides in transgenic Caenorhabditis elegans. Journal of Neuroscience. 2006;26(50).","DOI":"10.1523\/JNEUROSCI.3448-06.2006"},{"key":"2026073102551235000_2026.07.27.740981v1.15","doi-asserted-by":"crossref","unstructured":"Kato S , Kaplan HS , Schr\u00f6del T , Skora S , Lindsay TH , Yemini E , et al. Global Brain Dynamics Embed the Motor Command Sequence of Caenorhabditis elegans. Cell. 2015;163(3).","DOI":"10.1016\/j.cell.2015.09.034"},{"key":"2026073102551235000_2026.07.27.740981v1.16","doi-asserted-by":"crossref","unstructured":"Rand JB . Acetylcholine (January 30, 2007). In: WormBook, ed The C elegans Research Community, WormBook, doi\/101895\/wormbook11311, http:\/\/www.wormbook.org. 2007.","DOI":"10.1895\/wormbook.1.131.1"},{"key":"2026073102551235000_2026.07.27.740981v1.17","doi-asserted-by":"crossref","unstructured":"Mahoney TR , Luo S , Nonet ML . Analysis of synaptic transmission in Caenorhabditis elegans using an aldicarb-sensitivity assay. Nat Protoc. 2006;1(4).","DOI":"10.1038\/nprot.2006.281"},{"key":"2026073102551235000_2026.07.27.740981v1.18","doi-asserted-by":"crossref","unstructured":"Zeisel SH . Metabolic crosstalk between choline\/1-carbon metabolism and energy homeostasis. In: Clinical Chemistry and Laboratory Medicine. 2013.","DOI":"10.1515\/cclm-2012-0518"},{"key":"2026073102551235000_2026.07.27.740981v1.19","doi-asserted-by":"crossref","unstructured":"Borro M , Cavallaro RA , Gentile G , Nicolia V , Fuso A , Simmaco M , et al. One-carbon metabolism alteration affects brain proteome profile in a mouse model of Alzheimer\u2019s disease. Journal of Alzheimer\u2019s Disease. 2010;22(4).","DOI":"10.3233\/JAD-2010-101107"},{"key":"2026073102551235000_2026.07.27.740981v1.20","doi-asserted-by":"crossref","unstructured":"Joshi SM , Jadavji NM . Deficiencies in one-carbon metabolism led to increased neurological disease risk and worse outcome: homocysteine is a marker of disease state. Vol. 11, Frontiers in Nutrition. 2024.","DOI":"10.3389\/fnut.2024.1285502"},{"key":"2026073102551235000_2026.07.27.740981v1.21","doi-asserted-by":"crossref","unstructured":"Lionaki E , Ploumi C , Tavernarakis N . One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration. Vol. 11, Cells. 2022.","DOI":"10.3390\/cells11020214"},{"key":"2026073102551235000_2026.07.27.740981v1.22","doi-asserted-by":"crossref","unstructured":"Figueroa-Gonz\u00e1lez G , Silva-Adaya D , Corona-Trejo A , Gonsebatt ME , Trejo-Solis C , Campos-Pe\u00f1a V , et al. Transsulfuration pathway: a targeting neuromodulator in Parkinson\u2019s disease. Rev Neurosci. 2023;34(8).","DOI":"10.1515\/revneuro-2023-0039"},{"key":"2026073102551235000_2026.07.27.740981v1.23","doi-asserted-by":"crossref","unstructured":"Paul BD . Neuroprotective Roles of the Reverse Transsulfuration Pathway in Alzheimer\u2019s Disease. Vol. 13, Frontiers in Aging Neuroscience. 2021.","DOI":"10.3389\/fnagi.2021.659402"},{"key":"2026073102551235000_2026.07.27.740981v1.24","doi-asserted-by":"crossref","unstructured":"Umekar M , Premchandani T , Tatode A , Qutub M , Raut N , Taksande J , et al. Vitamin B12 deficiency and cognitive impairment: A comprehensive review of neurological impact. Vol. 18, Brain Disorders. Elsevier B.V.; 2025.","DOI":"10.1016\/j.dscb.2025.100220"},{"key":"2026073102551235000_2026.07.27.740981v1.25","doi-asserted-by":"crossref","unstructured":"Luthra NS , Marcus AH , Hills NK , Christine CW . Vitamin B12 measurements across neurodegenerative disorders. J Clin Mov Disord. 2020;7(1).","DOI":"10.1186\/s40734-020-00085-8"},{"key":"2026073102551235000_2026.07.27.740981v1.26","doi-asserted-by":"crossref","unstructured":"Bonvento G , Oliet SHR , Panatier A . Glycolysis-derived L-serine levels versus PHGDH expression in Alzheimer\u2019s disease. Vol. 34, Cell Metabolism. 2022.","DOI":"10.1016\/j.cmet.2022.04.002"},{"key":"2026073102551235000_2026.07.27.740981v1.27","doi-asserted-by":"crossref","unstructured":"Le Douce J , Maugard M , Veran J , Matos M , J\u00e9go P , Vigneron PA , et al. Impairment of Glycolysis-Derived L-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer\u2019s Disease. Cell Metab. 2020;31(3).","DOI":"10.1016\/j.cmet.2020.02.004"},{"key":"2026073102551235000_2026.07.27.740981v1.28","doi-asserted-by":"crossref","unstructured":"Ni X , Inoue R , Wu Y , Yoshida T , Yaku K , Nakagawa T , et al. Regional contributions of D-serine to Alzheimer\u2019s disease pathology in male AppNL\u2013G\u2013F\/NL\u2013G\u2013F mice. Front Aging Neurosci. 2023;15.","DOI":"10.3389\/fnagi.2023.1211067"},{"key":"2026073102551235000_2026.07.27.740981v1.29","doi-asserted-by":"crossref","unstructured":"Huang YC , Pirri JK , Rayes D , Gao S , Mulcahy B , Grant J , et al. Gain-of-function mutations in the UNC-2\/CaV2\u03b1 channel lead to excitation-dominant synaptic transmission in C. elegans. Elife. 2019;8.","DOI":"10.7554\/eLife.45905"},{"key":"2026073102551235000_2026.07.27.740981v1.30","doi-asserted-by":"crossref","unstructured":"Bukke VN , Archana M , Villani R , Romano AD , Wawrzyniak A , Balawender K , et al. The dual role of glutamatergic neurotransmission in Alzheimer\u2019s disease: From pathophysiology to pharmacotherapy. Vol. 21, International Journal of Molecular Sciences. 2020.","DOI":"10.3390\/ijms21207452"},{"key":"2026073102551235000_2026.07.27.740981v1.31","doi-asserted-by":"crossref","unstructured":"Liu J , Chang L , Song Y , Li H , Wu Y . The role of NMDA receptors in Alzheimer\u2019s disease. Vol. 13, Frontiers in Neuroscience. 2019.","DOI":"10.3389\/fnins.2019.00043"},{"key":"2026073102551235000_2026.07.27.740981v1.32","doi-asserted-by":"crossref","unstructured":"Liu W , Li Y , Zhao T , Gong M , Wang X , Zhang Y , et al. The role of N-methyl-D-aspartate glutamate receptors in Alzheimer\u2019s disease: From pathophysiology to therapeutic approaches. Vol. 231, Progress in Neurobiology. 2023.","DOI":"10.1016\/j.pneurobio.2023.102534"},{"key":"2026073102551235000_2026.07.27.740981v1.33","doi-asserted-by":"crossref","unstructured":"Nelson SB , Valakh V . Excitatory\/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders. Vol. 87, Neuron. 2015.","DOI":"10.1016\/j.neuron.2015.07.033"},{"key":"2026073102551235000_2026.07.27.740981v1.34","doi-asserted-by":"crossref","unstructured":"Hampel H , Mesulam MM , Cuello AC , Khachaturian AS , Vergallo A , Farlow MR , et al. Revisiting the Cholinergic Hypothesis in Alzheimer\u2019s Disease: Emerging Evidence from Translational and Clinical Research. Vol. 6, The journal of prevention of Alzheimer\u2019s disease. 2019.","DOI":"10.14283\/jpad.2018.43"},{"key":"2026073102551235000_2026.07.27.740981v1.35","doi-asserted-by":"crossref","unstructured":"Chen ZR , Huang JB , Yang SL , Hong FF . Role of Cholinergic Signaling in Alzheimer\u2019s Disease. Vol. 27, Molecules. 2022.","DOI":"10.3390\/molecules27061816"},{"key":"2026073102551235000_2026.07.27.740981v1.36","doi-asserted-by":"crossref","unstructured":"Ionescu-Tucker A , Cotman CW . Emerging roles of oxidative stress in brain aging and Alzheimer\u2019s disease. Vol. 107, Neurobiology of Aging. 2021.","DOI":"10.1016\/j.neurobiolaging.2021.07.014"},{"key":"2026073102551235000_2026.07.27.740981v1.37","doi-asserted-by":"crossref","unstructured":"Obeid R , Herrmann W . Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. Vol. 580, FEBS Letters. 2006.","DOI":"10.1016\/j.febslet.2006.04.088"},{"key":"2026073102551235000_2026.07.27.740981v1.38","doi-asserted-by":"crossref","unstructured":"Chen X , Calandrelli R , Girardini J , Yan Z , Tan Z , Xu X , et al. PHGDH expression increases with progression of Alzheimer\u2019s disease pathology and symptoms. Vol. 34, Cell Metabolism. 2022.","DOI":"10.1101\/2022.02.15.480384"},{"key":"2026073102551235000_2026.07.27.740981v1.39","doi-asserted-by":"crossref","unstructured":"Yadav DK , Chang AC , Grooms NW , Chung SH , Gabel C V . O-GlcNAc signaling increases neuron regeneration through one-carbon metabolism in Caenorhabditis elegans. Elife. 2024 Feb 9;13.","DOI":"10.7554\/eLife.86478"},{"key":"2026073102551235000_2026.07.27.740981v1.40","doi-asserted-by":"crossref","unstructured":"Umekar M , Premchandani T , Tatode A , Qutub M , Raut N , Taksande J , et al. Vitamin B12 deficiency and cognitive impairment: A comprehensive review of neurological impact. Vol. 18, Brain Disorders. Elsevier B.V.; 2025.","DOI":"10.1016\/j.dscb.2025.100220"},{"key":"2026073102551235000_2026.07.27.740981v1.41","doi-asserted-by":"crossref","unstructured":"Tawfik A , Elsherbiny NM , Zaidi Y , Rajpurohit P . Homocysteine and age-related central nervous system diseases: Role of inflammation. Vol. 22, International Journal of Molecular Sciences. 2021.","DOI":"10.3390\/ijms22126259"},{"key":"2026073102551235000_2026.07.27.740981v1.42","doi-asserted-by":"crossref","unstructured":"Luzzi S , Cherubini V , Falsetti L , Viticchi G , Silvestrini M , Toraldo A . Homocysteine, Cognitive Functions, and Degenerative Dementias: State of the Art. Vol. 10, Biomedicines. 2022.","DOI":"10.3390\/biomedicines10112741"},{"key":"2026073102551235000_2026.07.27.740981v1.43","doi-asserted-by":"crossref","unstructured":"Hooshmand B , Refsum H , Smith AD , Kalpouzos G , Mangialasche F , Von Arnim CAF , et al. Association of Methionine to Homocysteine Status with Brain Magnetic Resonance Imaging Measures and Risk of Dementia. JAMA Psychiatry. 2019;76(11).","DOI":"10.1001\/jamapsychiatry.2019.1694"},{"key":"2026073102551235000_2026.07.27.740981v1.44","doi-asserted-by":"crossref","unstructured":"Tackenberg C , Grinschgl S , Trutzel A , Santuccione AC , Frey MC , Konietzko U , et al. NMDA receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss. Cell Death Dis. 2013;4(4).","DOI":"10.1038\/cddis.2013.129"},{"key":"2026073102551235000_2026.07.27.740981v1.45","doi-asserted-by":"crossref","unstructured":"Gu Z , Cheng J , Zhong P , Qin L , Liu W , Yan Z . A\u03b2 selectively impairs mGluR7 modulation of NMDA signaling in basal forebrain cholinergic neurons: Implication in alzheimer\u2019s disease. Journal of Neuroscience. 2014;34(41).","DOI":"10.1523\/JNEUROSCI.1204-14.2014"},{"key":"2026073102551235000_2026.07.27.740981v1.46","doi-asserted-by":"crossref","unstructured":"Smulan LJ , Ding W , Freinkman E , Gujja S , Edwards YJK , Walker AK . Cholesterol-Independent SREBP-1 Maturation Is Linked to ARF1 Inactivation. Cell Rep. 2016;16(1).","DOI":"10.1016\/j.celrep.2016.05.086"},{"key":"2026073102551235000_2026.07.27.740981v1.47","doi-asserted-by":"crossref","unstructured":"Oh K , Kim H . Aldicarb-induced Paralysis Assay to Determine Defects in Synaptic Transmission in Caenorhabditis elegans. Bio Protoc. 2017;7(14).","DOI":"10.21769\/BioProtoc.2400"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.27.740981","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T09:55:31Z","timestamp":1785491731000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.07.27.740981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":47,"URL":"https:\/\/doi.org\/10.64898\/2026.07.27.740981","relation":{},"subject":[],"published":{"date-parts":[[2026,7,29]]},"subtype":"preprint"}}