{"id":"https://openalex.org/W7225008288","doi":"https://doi.org/10.5281/zenodo.23833397","title":"PADA-V2 Addendum Photoperiod\u2013Adenosine\u2013Desensitization\u2013Aging: Mechanistic Completion, Tier Re-classification, and Supplementary Experimental Design","display_name":"PADA-V2 Addendum Photoperiod\u2013Adenosine\u2013Desensitization\u2013Aging: Mechanistic Completion, Tier Re-classification, and Supplementary Experimental Design","publication_year":2026,"publication_date":"2026-10-31","ids":{"openalex":"https://openalex.org/W7225008288","doi":"https://doi.org/10.5281/zenodo.23833397"},"language":"en","primary_location":{"id":"doi:10.5281/zenodo.23833397","doi":"https://doi.org/10.5281/zenodo.23833397","is_oa":true,"landing_page_url":"https://doi.org/10.5281/zenodo.23833397","pdf_url":null,"source":{"id":"https://openalex.org/S4306400562","display_name":"Zenodo (CERN European Organization for Nuclear Research)","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I67311998","host_organization_name":"European Organization for Nuclear Research","host_organization_lineage":["https://openalex.org/I67311998"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":null,"is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"Preprint"},"volume":null,"type":"preprint","indexed_in":["datacite"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://doi.org/10.5281/zenodo.23833397","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5048078482","display_name":"Billy Ma","orcid":"https://orcid.org/0009-0003-7695-9453","observed_orcids":["https://orcid.org/0009-0003-7695-9453"]},"institutions":[],"countries":[],"is_corresponding":true,"raw_author_name":"Ma, Billy","raw_affiliation_strings":[],"raw_orcid":null,"affiliations":[]}],"institutions":[],"countries_distinct_count":0,"institutions_distinct_count":0,"corresponding_author_ids":["https://openalex.org/A5048078482"],"corresponding_institution_ids":[],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10342","display_name":"Circadian rhythm and melatonin","score":0.7470999956130981,"subfield":{"id":"https://openalex.org/subfields/2807","display_name":"Endocrine and Autonomic Systems"},"field":{"id":"https://openalex.org/fields/28","display_name":"Neuroscience"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T10342","display_name":"Circadian rhythm and melatonin","score":0.7470999956130981,"subfield":{"id":"https://openalex.org/subfields/2807","display_name":"Endocrine and Autonomic Systems"},"field":{"id":"https://openalex.org/fields/28","display_name":"Neuroscience"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10985","display_name":"Sleep and Wakefulness Research","score":0.17239999771118164,"subfield":{"id":"https://openalex.org/subfields/2805","display_name":"Cognitive Neuroscience"},"field":{"id":"https://openalex.org/fields/28","display_name":"Neuroscience"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11193","display_name":"Adenosine and Purinergic Signaling","score":0.022099999710917473,"subfield":{"id":"https://openalex.org/subfields/1314","display_name":"Physiology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/adenosine-receptors","display_name":"adenosine receptors","score":0.6940000057220459},{"id":"https://openalex.org/keywords/g-protein-coupled-receptor-desensitization","display_name":"G protein-coupled receptor desensitization","score":0.8730000257492065},{"id":"https://openalex.org/keywords/homologous-desensitization","display_name":"homologous desensitization","score":0.7990000247955322},{"id":"https://openalex.org/keywords/adenosine-a2a-receptor","display_name":"adenosine A2A receptor","score":0.6650000214576721},{"id":"https://openalex.org/keywords/nf-kappab-signaling","display_name":"NF-\u03baB signaling","score":0.8339999914169312},{"id":"https://openalex.org/keywords/microglial-inflammation","display_name":"microglial inflammation","score":0.7889999747276306},{"id":"https://openalex.org/keywords/aging","display_name":"aging","score":0.6209999918937683},{"id":"https://openalex.org/keywords/sleep-pressure","display_name":"sleep pressure","score":0.6359999775886536},{"id":"https://openalex.org/keywords/subjective-sleepiness","display_name":"subjective sleepiness","score":0.5370000004768372},{"id":"https://openalex.org/keywords/photoperiod","display_name":"photoperiod","score":0.6980000138282776},{"id":"https://openalex.org/keywords/scandium-nitride","display_name":"scandium nitride","score":0.5410000085830688},{"id":"https://openalex.org/keywords/melatonin","display_name":"melatonin","score":0.9819999933242798},{"id":"https://openalex.org/keywords/beta-arrestin-signaling","display_name":"\u03b2-arrestin signaling","score":0.5839999914169312}],"concepts":[{"id":"https://openalex.org/C2779779143","wikidata":"https://www.wikidata.org/wiki/Q3493547","display_name":"Desensitization (medicine)","level":3,"score":0.5946000218391418},{"id":"https://openalex.org/C135285700","wikidata":"https://www.wikidata.org/wiki/Q38173","display_name":"G protein-coupled receptor","level":3,"score":0.5467000007629395},{"id":"https://openalex.org/C92759361","wikidata":"https://www.wikidata.org/wiki/Q5891436","display_name":"Homologous desensitization","level":4,"score":0.5097000002861023},{"id":"https://openalex.org/C170493617","wikidata":"https://www.wikidata.org/wiki/Q208467","display_name":"Receptor","level":2,"score":0.4772000014781952},{"id":"https://openalex.org/C34146451","wikidata":"https://www.wikidata.org/wiki/Q5048094","display_name":"Cascade","level":2,"score":0.4496999979019165},{"id":"https://openalex.org/C2776991684","wikidata":"https://www.wikidata.org/wiki/Q190012","display_name":"Adenosine","level":2,"score":0.4447999894618988},{"id":"https://openalex.org/C67907053","wikidata":"https://www.wikidata.org/wiki/Q356147","display_name":"Adenosine receptor","level":4,"score":0.4368000030517578},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.429500013589859},{"id":"https://openalex.org/C182365436","wikidata":"https://www.wikidata.org/wiki/Q50701","display_name":"Variable (mathematics)","level":2,"score":0.4259999990463257},{"id":"https://openalex.org/C169760540","wikidata":"https://www.wikidata.org/wiki/Q207011","display_name":"Neuroscience","level":1,"score":0.4189999997615814},{"id":"https://openalex.org/C41008148","wikidata":"https://www.wikidata.org/wiki/Q21198","display_name":"Computer science","level":0,"score":0.4163999855518341},{"id":"https://openalex.org/C70721500","wikidata":"https://www.wikidata.org/wiki/Q177005","display_name":"Computational biology","level":1,"score":0.3695000112056732},{"id":"https://openalex.org/C131584629","wikidata":"https://www.wikidata.org/wiki/Q4308705","display_name":"Coupling (piping)","level":2,"score":0.3465000092983246},{"id":"https://openalex.org/C116569031","wikidata":"https://www.wikidata.org/wiki/Q899107","display_name":"Ligand (biochemistry)","level":3,"score":0.3255000114440918},{"id":"https://openalex.org/C186060115","wikidata":"https://www.wikidata.org/wiki/Q30336093","display_name":"Biological system","level":1,"score":0.29499998688697815},{"id":"https://openalex.org/C12554922","wikidata":"https://www.wikidata.org/wiki/Q7100","display_name":"Biophysics","level":1,"score":0.27630001306533813},{"id":"https://openalex.org/C2777021972","wikidata":"https://www.wikidata.org/wiki/Q22976830","display_name":"Uniqueness","level":2,"score":0.27489998936653137},{"id":"https://openalex.org/C12426560","wikidata":"https://www.wikidata.org/wiki/Q189569","display_name":"Basis (linear algebra)","level":2,"score":0.27480000257492065},{"id":"https://openalex.org/C33923547","wikidata":"https://www.wikidata.org/wiki/Q395","display_name":"Mathematics","level":0,"score":0.25760000944137573}],"mesh":[],"locations_count":2,"locations":[{"id":"doi:10.5281/zenodo.23833397","doi":"https://doi.org/10.5281/zenodo.23833397","is_oa":true,"landing_page_url":"https://doi.org/10.5281/zenodo.23833397","pdf_url":null,"source":{"id":"https://openalex.org/S4306400562","display_name":"Zenodo (CERN European Organization for Nuclear Research)","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I67311998","host_organization_name":"European Organization for Nuclear Research","host_organization_lineage":["https://openalex.org/I67311998"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":null,"is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"Preprint"},{"id":"doi:10.5281/zenodo.23833398","doi":"https://doi.org/10.5281/zenodo.23833398","is_oa":true,"landing_page_url":"https://doi.org/10.5281/zenodo.23833398","pdf_url":null,"source":{"id":"https://openalex.org/S4306400562","display_name":"Zenodo (CERN European Organization for Nuclear Research)","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I67311998","host_organization_name":"European Organization for Nuclear Research","host_organization_lineage":["https://openalex.org/I67311998"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":null,"is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"Preprint"}],"best_oa_location":{"id":"doi:10.5281/zenodo.23833397","doi":"https://doi.org/10.5281/zenodo.23833397","is_oa":true,"landing_page_url":"https://doi.org/10.5281/zenodo.23833397","pdf_url":null,"source":{"id":"https://openalex.org/S4306400562","display_name":"Zenodo (CERN European Organization for Nuclear Research)","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I67311998","host_organization_name":"European Organization for Nuclear Research","host_organization_lineage":["https://openalex.org/I67311998"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":null,"is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"Preprint"},"sustainable_development_goals":[{"score":0.428600013256073,"display_name":"Good health and well-being","id":"https://metadata.un.org/sdg/3"}],"study_designs":[],"awards":[],"funders":[],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W7204081934","https://openalex.org/W7204047254","https://openalex.org/W7212194315","https://openalex.org/W7212132569","https://openalex.org/W1974474847","https://openalex.org/W2279047711","https://openalex.org/W2077003283","https://openalex.org/W2069502746","https://openalex.org/W2582466908","https://openalex.org/W2545162576"],"abstract_inverted_index":{"Background.":[0],"The":[1,47,212,244,286,445,493],"PADA":[2],"hypothesis":[3],"proposes":[4],"that":[5,220,530],"adenosine-mediated":[6],"subjective":[7],"sleep":[8],"pressure":[9],"and":[10,29,64,99,115,167,172,189,228,235,257,291,304,338,347,352,367,388,395,419,487,501,507,535],"acute":[11,186],"cellular":[12,454],"stress":[13],"are":[14,428,483,488],"not":[15,104,464,489,497,562],"determined":[16],"by":[17,26,325,379],"the":[18,30,37,53,57,108,128,132,143,152,199,206,276,307,313,319,373,433,441,456,467,469,475,499,533,537,541,577],"absolute":[19],"extracellular":[20],"adenosine":[21,35,476],"concentration":[22,28],"alone,":[23],"but":[24],"jointly":[25],"ligand":[27],"G-protein":[31,187],"coupling":[32],"state":[33],"of":[34,131,142,185,198,223,279,301,345,432,448,458,471,474,504,540,546],"receptors,":[36],"latter":[38],"quantified":[39],"as":[40,84,176,270,296,312,397,485,491,515],"a":[41,60,65,85,147,177,181,190,253,259,297,333,353,358,398,516,551],"GRK-mediated":[42],"homologous":[43],"desensitization":[44,159,267],"level":[45],"D.":[46],"parent":[48,109,144,153,578],"manuscript":[49,110,145,579],"(PADA-V2,":[50],"2026-08)":[51],"established":[52],"photoperiod\u2013SCN\u2013melatonin\u2013adenosine":[54],"(P-S-M-A)":[55],"axis,":[56],"variable":[58,87,179],"D,":[59],"four-tier":[61],"inference":[62,256],"scheme,":[63],"three-stage":[66],"experimental":[67,556],"programme.":[68],"It":[69,560],"nevertheless":[70],"left":[71],"four":[72,133,403],"structural":[73,517],"gaps:":[74],"downstream":[75,331],"cascades":[76],"were":[77],"described":[78],"only":[79,239,451],"phenomenologically;":[80],"D":[81,173],"was":[82,97,103],"treated":[83],"single":[86],"without":[88,150,554],"distinguishing":[89],"reversible":[90],"from":[91],"quasi-irreversible":[92],"desensitization;":[93],"brain-region":[94],"receptor":[95,202,242],"heterogeneity":[96],"omitted;":[98],"hypothalamic":[100],"sleep-executive":[101],"circuitry":[102],"integrated.":[105],"In":[106],"addition,":[107],"contains":[111],"several":[112],"statement-level":[113],"errors":[114],"one":[116,271],"directional":[117],"contradiction.":[118],"Objective.":[119],"This":[120,204,523,549,570],"document":[121],"performs":[122],"two":[123],"functions.":[124],"First,":[125],"it":[126,136],"completes":[127],"mechanistic":[129],"treatment":[130],"gaps.":[134],"Second,":[135],"formally":[137],"supersedes":[138],"nine":[139],"identified":[140],"defects":[141],"through":[146],"parallel-addendum-plus-clause-supersession":[148],"mechanism,":[149],"re-releasing":[151],"version.":[154],"Principal":[155],"extensions.":[156],"(1)":[157],"GPCR":[158],"is":[160,174,215,225,249,268,289,294,463,478,513,550],"separated":[161],"into":[162],"D\u2081":[163,303],"(membrane-retained,":[164],"rapidly":[165],"reversible)":[166],"D\u2082":[168],"(endocytic\u2013lysosomal,":[169],"slowly":[170],"reversible),":[171],"redefined":[175],"two-axis":[178],"comprising":[180],"benefit":[182],"axis":[183,192],"(attenuation":[184],"output)":[188],"cost":[191],"(residual":[193],"\u03b2-arrestin":[194],"signalling":[195],"plus":[196],"depletion":[197],"functional":[200,330],"surface":[201],"pool).":[203],"replaces":[205],"earlier":[207],"one-dimensional":[208],"higher-is-better-or-worse":[209],"formulation.":[210],"(2)":[211],"A\u2082A":[213,221,449],"cascade":[214,435],"dissected":[216],"with":[217,282,306,385,402,414,576],"explicit":[218],"acknowledgement":[219],"modulation":[222,262,473],"NF-\u03baB":[224],"strongly":[226],"cell-type-":[227],"time-dependent\u2014predominantly":[229],"anti-inflammatory":[230],"in":[231,237,320,374,440,466],"peripheral":[232,415],"immune":[233,500],"cells,":[234],"pro-inflammatory":[236,446],"microglia":[238],"after":[240],"sustained":[241],"up-regulation.":[243],"previously":[245,527],"proposed":[246,269,434],"\u201caging":[247],"amplifier\u201d":[248],"therefore":[250],"demoted":[251],"to":[252,349,411,421],"conditional":[254,260,393],"second-tier":[255],"renamed":[258],"aging-signal":[261],"axis.":[263],"(3)":[264],"Brain-region":[265],"asynchronous":[266],"non-exclusive":[272],"candidate":[273],"explanation":[274],"for":[275],"dissociated":[277],"phenotype":[278],"somatic":[280],"fatigue":[281],"cerebral":[283],"hyper-arousal.":[284],"(4)":[285],"VLPO\u2013TMN":[287],"circuit":[288],"integrated,":[290],"Process-S":[292],"output":[293],"restated":[295],"qualitative":[298],"multivariate":[299],"function":[300],"adenosine,":[302],"D\u2082,":[305],"classical":[308],"single-variable":[309],"formulation":[310],"recovered":[311],"D\u21920":[314],"limit.":[315],"Methodological":[316],"additions.":[317],"At":[318,372],"vitro":[321],"level:":[322,376],"D\u2081/D\u2082":[323],"discrimination":[324],"three":[326,482],"convergent":[327],"evidence":[328],"chains,":[329],"readouts,":[332],"side-path/main-path":[334],"ratio":[335],"R,":[336],"SASP":[337],"mTOR-axis":[339],"markers":[340],"(with":[341],"mandatory":[342,386],"parallel":[343],"assessment":[344],"p-AMPK":[346],"p-TSC2":[348],"resolve":[350],"direction),":[351],"continuous-versus-pulsatile":[354],"contrast":[355],"built":[356],"on":[357,461],"pre-registered":[359],"dose\u2013time":[360],"matrix":[361],"(peak,":[362],"frequency,":[363],"duty":[364],"cycle,":[365],"AUC,":[366],"five":[368],"recovery":[369],"sampling":[370,378],"points).":[371],"vivo":[375],"region-resolved":[377],"laser":[380],"microdissection":[381],"or":[382,557,567],"fibre":[383],"photometry":[384],"normalization,":[387],"A\u2082A-KO,":[389],"A\u2081-KO,":[390],"GRK2/3":[391],"central":[392],"knockout":[394],"\u03b2-arrestin2-KO":[396],"core":[399],"falsification":[400],"arm":[401],"separately":[404],"adjudicable":[405],"outcomes.":[406],"Human":[407],"work":[408],"remains":[409],"restricted":[410],"observational":[412],"cohorts,":[413],"surrogates":[416],"explicitly":[417],"graded":[418],"limited":[420],"correlational":[422],"inference.":[423],"Self-limitation.":[424],"No":[425,430],"original":[426,555],"data":[427],"presented.":[429],"component":[431],"has":[436],"been":[437],"measured":[438],"simultaneously":[439],"living":[442],"human":[443],"brain.":[444],"direction":[447,457,470],"holds":[450],"under":[452],"defined":[453],"conditions;":[455],"cAMP\u2013PKA":[459],"action":[460],"mTORC1":[462],"settled":[465],"field;":[468],"photoperiodic":[472],"system":[477],"likewise":[479],"undetermined.":[480],"All":[481],"flagged":[484],"direction-pending":[486],"used":[490],"conclusions.":[492],"framework":[494],"also":[495],"does":[496,561],"address":[498],"metabolic":[502],"functions":[503],"sleep\u2014an":[505],"independent":[506],"plausibly":[508],"more":[509],"important":[510],"dimension\u2014and":[511],"this":[512,547],"declared":[514],"blind":[518],"spot":[519],"rather":[520],"than":[521],"defended.":[522],"revision":[524],"adds":[525],"six":[526],"unlisted":[528],"limitations":[529],"argue":[531],"against":[532],"hypothesis,":[534],"withdraws":[536],"right-hand":[538],"limb":[539],"sleep-duration":[542],"U-curve":[543],"outright.":[544],"Nature":[545],"document.":[548],"falsifiable-hypothesis":[552],"archive":[553],"clinical":[558],"data.":[559],"constitute":[563],"medical,":[564],"therapeutic,":[565],"sleep-timing":[566],"light-exposure":[568],"advice.":[569],"addendum":[571],"should":[572],"be":[573],"cited":[574],"together":[575],"PADA-V2.":[580]},"counts_by_year":[],"updated_date":"2026-11-02T09:45:03.842371","created_date":"2026-11-01T00:00:00"}