I. Hoolauna
ʻO Phospholipids kahi papa o nā lipid he mau mea koʻikoʻi o nā membrane cell. ʻO kā lākou hana kūikawā, kahi poʻo hydrophilic a me ʻelua huelo hydrophobic, hiki i nā phospholipids ke hana i kahi ʻano bilayer, e lawelawe ana ma ke ʻano he pale e hoʻokaʻawale i nā mea i loko o ka cell mai ka ʻaoʻao o waho. He mea nui kēia hana kūkulu no ka mālama ʻana i ka pono a me ka hana o nā cell i nā mea ola a pau.
ʻO ka hōʻailona kelepona a me ke kamaʻilio ʻana he mau hana koʻikoʻi e hiki ai i nā cell ke launa pū kekahi me ko lākou kaiapuni, e ʻae ana i nā pane i hoʻonohonoho ʻia i nā ʻano hoʻoulu. Hiki i nā pūnaewele ke hoʻoponopono i ka ulu, hoʻomohala, a me nā hana physiological he nui ma o kēia mau kaʻina. ʻO nā ala hōʻailona kelepona e pili ana i ka lawe ʻana i nā hōʻailona, e like me nā hormones a i ʻole nā neurotransmitters, i ʻike ʻia e nā mea hoʻokipa ma ka membrane cell, e hoʻoulu i kahi cascade o nā hanana e alakaʻi i kahi pane kelepona kikoʻī.
He mea koʻikoʻi ka hoʻomaopopo ʻana i ke kuleana o ka phospholipids i ka hōʻailona kelepona a me ke kamaʻilio ʻana no ka wehe ʻana i nā paʻakikī o ke ʻano o ke kamaʻilio ʻana a me ka hoʻonohonoho ʻana i kā lākou mau hana. Loaʻa ka hopena o kēia ʻike ma nā ʻano like ʻole, me ka biology cell, pharmacology, a me ka hoʻomohala ʻana i nā lāʻau lapaʻau i manaʻo ʻia no nā maʻi a me nā maʻi he nui. Ma ka ʻimi ʻana i ka pilina paʻakikī ma waena o ka phospholipids a me ka hōʻailona cell, hiki iā mākou ke loaʻa nā ʻike i nā kaʻina kumu e hoʻokele ai i ka ʻano a me ka hana o ka cellular.
II. Kapili o Phospholipids
A. ʻO ka wehewehe ʻana o ka Phospholipid Structure:
ʻO ka Phospholipids nā molekole amphipathic, ʻo ia hoʻi, loaʻa iā lākou nā ʻāpana hydrophilic (ka huki wai) a me nā ʻāpana hydrophobic (wai-repelling). ʻO ke ʻano kumu o ka phospholipid kahi mole glycerol i hoʻopaʻa ʻia i ʻelua mau kaulahao momona a me kahi pūʻulu poʻo phosphate. ʻO nā huelo hydrophobic, i haku ʻia me nā kaulahao momona momona, e hana i loko o ka lipid bilayer, aʻo nā hui poʻo hydrophilic e hui pū me ka wai ma nā ʻaoʻao o loko a me waho o ka membrane. ʻO kēia hoʻonohonoho kūʻokoʻa e hiki ai i nā phospholipids ke hōʻuluʻulu iā lākou iho i kahi bilayer, me nā huelo hydrophobic e kuhikuhi ana i loko a me nā poʻo hydrophilic e kū pono ana i nā kaiapuni wai i loko a i waho o ke kelepona.
B. Ke kuleana o ka Phopholipid Bilayer i loko o ka membrane cell:
ʻO ka phospholipid bilayer he mea hana koʻikoʻi o ka membrane cell, e hāʻawi ana i kahi pale semi-permeable e hoʻomalu i ke kahe o nā mea i loko a i waho o ke kelepona. He mea koʻikoʻi kēia permeability koho no ka mālama ʻana i ke kaiapuni o loko o ke kelepona a he mea koʻikoʻi ia no nā kaʻina hana e like me ka lawe ʻana i ka meaʻai, ka hoʻopau ʻana i ka ʻōpala, a me ka pale ʻana i nā mea ʻino. Ma waho aʻe o kāna hana hoʻolālā, hoʻokani ka phospholipid bilayer i kahi hana koʻikoʻi i ka hōʻailona kelepona a me ke kamaʻilio.
ʻO ke kumu hoʻohālike wai mosaic o ka membrane cell, i manaʻo ʻia e Singer lāua ʻo Nicolson i ka makahiki 1972, e hōʻike ana i ke ʻano ikaika a heterogeneous o ka membrane, me nā phospholipids e neʻe mau ana a me nā protein like ʻole i hoʻopuehu ʻia i loko o ka lipid bilayer. He mea nui kēia ʻano hoʻoikaika i ka hoʻomaʻamaʻa ʻana i ka hōʻailona kelepona a me ke kamaʻilio. Hoʻokomo ʻia nā mea hoʻokipa, nā kaila ion, a me nā protein hōʻailona ʻē aʻe i loko o ka phospholipid bilayer a he mea nui ia no ka ʻike ʻana i nā hōʻailona o waho a hoʻouna iā lākou i loko o ke kelepona.
Eia kekahi, ʻo nā waiwai kino o nā phospholipids, e like me ko lākou wai a me ka hiki ke hana i nā lipid rafts, e hoʻoikaika i ka hoʻonohonoho ʻana a me ka hana ʻana o nā protein membrane e pili ana i ka hōʻailona cell. Hoʻopili ka hana ikaika o ka phospholipids i ka localization a me ka hana o nā protein hōʻailona, no laila e hoʻopilikia i ka kikoʻī a me ka pono o nā ala hōʻailona.
ʻO ka hoʻomaopopo ʻana i ka pilina ma waena o nā phospholipids a me ke ʻano a me ka hana o ka membrane cell he mau hopena koʻikoʻi no nā kaʻina olaola he nui, me ka homeostasis cellular, ka ulu ʻana, a me nā maʻi. Ke hoʻomau nei ka hoʻohui ʻana o ka biology phospholipid me ka noiʻi hōʻailona cell e wehe i nā ʻike koʻikoʻi i ka paʻakikī o ke kamaʻilio kelepona a paʻa i ka ʻōlelo hoʻohiki no ka hoʻomohala ʻana i nā hoʻolālā therapeutic hou.
III. Ke kuleana o Phospholipids i ka hōʻailona kelepona
A. Phospholipids e like me nā molekule hōʻailona
ʻO Phospholipids, ma ke ʻano he mea koʻikoʻi o nā membrane cell, ua puka mai ma ke ʻano he molelika hōʻailona koʻikoʻi i ka kamaʻilio kelepona. ʻO nā pūʻulu poʻo hydrophilic o phospholipids, ʻoi aku ka nui o nā inositol phosphates, e lilo i mau ʻelele koʻikoʻi ma nā ala hōʻailona like ʻole. No ka laʻana, hana ka phosphatidylinositol 4,5-bisphosphate (PIP2) ma ke ʻano he molekele hōʻailona ma ka hoʻokaʻawale ʻana i loko o ka inositol trisphosphate (IP3) a me ka diacylglycerol (DAG) i ka pane ʻana i nā mea hoʻouluulu extracellular. He kuleana koʻikoʻi kēia mau molekala hōʻailona lipid i ka hoʻoponopono ʻana i nā pae calcium intracellular a me ka hoʻoulu ʻana i ka protein kinase C, no laila ke hoʻololi nei i nā kaʻina cellular like ʻole me ka hoʻonui ʻana o ka cell, ka ʻokoʻa, a me ka neʻe ʻana.
Eia kekahi, ua ʻike ʻia nā phospholipids e like me ka phosphatidic acid (PA) a me nā lysophospholipids e like me nā molekele hōʻailona e hoʻohuli pono i nā pane kelepona ma o ka launa pū ʻana me nā pahuhopu protein kikoʻī. No ka laʻana, hana ʻo PA ma ke ʻano he mea hoʻoponopono koʻikoʻi i ka ulu ʻana o ka cell a me ka hoʻonui ʻana ma ka hoʻoulu ʻana i nā protein hōʻailona, ʻoiai ka lysophosphatidic acid (LPA) i loko o ka hoʻoponopono ʻana o ka cytoskeletal dynamics, ke ola o ka cell, a me ka neʻe ʻana. ʻO kēia mau hana like ʻole o ka phospholipids e hōʻike i ko lākou koʻikoʻi i ka hoʻonohonoho ʻana i nā cascade hōʻailona paʻakikī i loko o nā cell.
B. Ke komo ʻana o nā Phospholipids i nā ala Transduction Signal
Hoʻohālikelike ʻia ke komo ʻana o nā phospholipids i nā ala transduction hōʻailona e ko lākou kuleana koʻikoʻi i ka hoʻololi ʻana i ka hana o nā mea i hoʻopaʻa ʻia i ka membrane, ʻoi aku ka G protein-coupled receptors (GPCRs). Ma luna o ka ligand i hoʻopaʻa ʻia i nā GPCR, hoʻāla ʻia ka phospholipase C (PLC), e alakaʻi ana i ka hydrolysis o PIP2 a me ka hanauna o IP3 a me DAG. Hoʻokumu ʻo IP3 i ka hoʻokuʻu ʻana o ka calcium mai nā hale kūʻai intracellular, ʻoiai ʻo DAG e hoʻāla i ka protein kinase C, i ka hopena i ka hoʻoponopono ʻana i ka hōʻike gene, ka ulu ʻana o ka cell, a me ka hoʻouna synaptic.
Eia kekahi, ʻo nā phosphoinositides, kahi papa o nā phospholipids, e lawelawe ma ke ʻano he kahua docking no ka hōʻailona ʻana i nā protein i komo i nā ala like ʻole, me nā mea e hoʻoponopono ana i ke kālepa membrane a me ka actin cytoskeleton dynamics. ʻO ka pilina ikaika ma waena o nā phosphoinositides a me kā lākou mau protein e pili ana e kōkua i ka hoʻoponopono spatial a me ke kino o nā hanana hōʻailona, a laila e hana ana i nā pane cellular i nā hoʻoulu extracellular.
ʻO ke komo ʻana o nā phospholipids i ka hōʻailona kelepona a me nā ala transduction hōʻailona e hōʻike ana i ko lākou koʻikoʻi ma ke ʻano he mea hoʻoponopono koʻikoʻi o ka homeostasis cellular a me ka hana.
IV. ʻO Phospholipids a me Intracellular Communication
A. Phospholipids i ka hōʻailona intracellular
ʻO Phospholipids, kahi papa o nā lipid i loaʻa i kahi pūʻulu phosphate, e pāʻani i nā kuleana koʻikoʻi i ka hōʻailona intracellular, e hoʻonohonoho ana i nā kaʻina kelepona like ʻole ma o kā lākou komo ʻana i nā cascades hōʻailona. ʻO kekahi laʻana koʻikoʻi ʻo ka phosphatidylinositol 4,5-bisphosphate (PIP2), kahi phospholipid i loaʻa i ka membrane plasma. I ka pane ʻana i nā mea hoʻouluulu extracellular, ua hoʻokaʻawale ʻia ka PIP2 i loko o ka inositol trisphosphate (IP3) a me ka diacylglycerol (DAG) e ka enzyme phospholipase C (PLC). Hoʻokumu ʻo IP3 i ka hoʻokuʻu ʻana o ka calcium mai nā hale kūʻai intracellular, ʻoiai ʻo DAG e hoʻāla i ka protein kinase C, i ka hopena e hoʻoponopono i nā hana cellular like ʻole e like me ka hoʻonui ʻana o ka cell, ka ʻokoʻa, a me ka hoʻonohonoho hou ʻana o ka cytoskeletal.
Hoʻohui ʻia, ua ʻike ʻia nā phospholipids ʻē aʻe, me ka phosphatidic acid (PA) a me lysophospholipids, he koʻikoʻi i ka hōʻailona intracellular. Hāʻawi ʻo PA i ka hoʻoponopono ʻana i ka ulu ʻana o ka cell a me ka hoʻonui ʻana ma o ka hana ʻana ma ke ʻano he mea hoʻoulu i nā protein hōʻailona like ʻole. Ua ʻike ʻia ʻo Lysophosphatidic acid (LPA) no kona komo ʻana i ka modulation o ke ola cell, migration, a me ka cytoskeletal dynamics. Hōʻike kēia mau ʻike i nā kuleana like ʻole a koʻikoʻi o nā phospholipids e like me nā molekala hōʻailona i loko o ke kelepona.
B. Ka pilina o Phospholipids me nā Proteins a me nā Receptors
Hoʻopili pū ʻia nā Phospholipids me nā protein a me nā mea hoʻokipa e hoʻololi i nā ala hōʻailona kelepona. ʻO ka mea nui, ʻo phosphoinositides, kahi pūʻulu o nā phospholipids, e lawelawe ma ke ʻano he kahua no ka hoʻoulu ʻana a me ka hoʻāla ʻana o nā protein hōʻailona. No ka laʻana, hana ka phosphatidylinositol 3,4,5-trisphosphate (PIP3) ma ke ʻano he mea hoʻoponopono koʻikoʻi o ka ulu ʻana o ka cell a me ka hoʻonui ʻana ma o ka hoʻoulu ʻana i nā protein i loaʻa i nā domain pleckstrin homology (PH) i ka membrane plasma, a laila hoʻomaka i nā hanana hōʻailona lalo. Eia kekahi, ʻo ka hui ikaika o nā phospholipids me nā protein hōʻailona a me nā mea loaʻa e ʻae i ka mana spatiotemporal pololei o nā hanana hōʻailona i loko o ke kelepona.
ʻO ka launa pū ʻana o nā phospholipids me nā protein a me nā mea loaʻa e hōʻike i ko lākou kuleana koʻikoʻi i ka modulation o nā ala hōʻailona intracellular, e hāʻawi hope ana i ka hoʻoponopono ʻana i nā hana cellular.
V. Hooponopono o Phospholipids i ka hoailona Cell
A. Nā Enzymes a me nā ala i komo i loko o ka Phospholipid Metabolism
Hoʻoponopono ikaika ʻia ka Phospholipids ma o kahi ʻoihana paʻakikī o nā enzymes a me nā ala, e hoʻohuli ana i kā lākou nui a me ka hana i ka hōʻailona kelepona. ʻO kekahi o ia ala e pili ana i ka synthesis a me ka huli ʻana o ka phosphatidylinositol (PI) a me kāna mau phosphorylated derivatives, i kapa ʻia ʻo phosphoinositides. ʻO ka Phosphatidylinositol 4-kinases a me ka phosphatidylinositol 4-phosphate 5-kinases he mau enzymes e hoʻokalakupua i ka phosphorylation o PI ma nā kūlana D4 a me D5, e hana ana i ka phosphatidylinositol 4-phosphate (PI4P) a me ka phosphatidylinositol 4,5-bisphosphate (PIP2), kēlā me kēia. ʻO ka mea like ʻole, phosphatases, e like me phosphatase a me tensin homolog (PTEN), dephosphorylate phosphoinositides, e hoʻoponopono ana i ko lākou pae a me ka hopena i ka hōʻailona kelepona.
Eia kekahi, ʻo ka de novo synthesis o nā phospholipids, ʻo ia hoʻi ka phosphatidic acid (PA), ua hoʻopili ʻia e nā enzymes e like me ka phospholipase D a me ka diacylglycerol kinase, aʻo kā lākou hoʻohaʻahaʻa ʻia e nā phospholipases, me ka phospholipase A2 a me ka phospholipase C. bioactive lipid mediators, e hoʻopilikia ana i nā kaʻina hana hōʻailona cell a hāʻawi i ka mālama ʻana i ka homeostasis cellular.
B. Ka hopena o ka hoʻoponopono Phospholipid i nā kaʻina hana hōʻailona kelepona
ʻO ka hoʻoponopono ʻana o nā phospholipids e hoʻokō i nā hopena hohonu i nā kaʻina hana hōʻailona cell ma o ka hoʻololi ʻana i nā hana o nā molekole hōʻailona koʻikoʻi a me nā ala. No ka laʻana, ʻo ka huli ʻana o ka PIP2 e ka phospholipase C e hoʻopuka i ka inositol trisphosphate (IP3) a me ka diacylglycerol (DAG), e alakaʻi ana i ka hoʻokuʻu ʻana o ka calcium intracellular a me ka hoʻoulu ʻana o ka protein kinase C, kēlā me kēia. Hoʻopili kēia cascade hōʻailona i nā pane cellular e like me ka neurotransmission, ka ʻiʻo ʻana o ka ʻiʻo, a me ka hoʻoulu ʻana o ka cell immune.
Eia kekahi, hoʻololi i nā pae o phosphoinositides e pili ana i ka hoʻopiʻi ʻana a me ka hoʻōla ʻana o nā protein effector i loaʻa nā lipid-binding domains, ka hopena i nā kaʻina e like me ka endocytosis, cytoskeletal dynamics, a me ka neʻe ʻana o ka cell. Hoʻohui ʻia, ʻo ka hoʻoponopono ʻana i nā pae PA e nā phospholipases a me nā phosphatases e hoʻopili ai i ka hoʻolaha ʻana o ka membrane, ka ulu ʻana o ka cell, a me nā ala hōʻailona lipid.
ʻO ka pilina ma waena o ka phospholipid metabolism a me ka hōʻailona cell e hōʻike ana i ke koʻikoʻi o ka hoʻoponopono phospholipid i ka mālama ʻana i ka hana cellular a me ka pane ʻana i nā mea hoʻouluulu extracellular.
VI. Ka hopena
A. ʻO ka hōʻuluʻulu o nā kuleana koʻikoʻi o Phospholipids i ka hōʻailona kelepona a me ka kamaʻilio
I ka hōʻuluʻulu ʻana, pāʻani nā phospholipids i nā kuleana koʻikoʻi i ka hoʻonohonoho ʻana i ka hōʻailona kelepona a me nā kaʻina kamaʻilio i loko o nā ʻōnaehana biological. ʻO kā lākou hoʻolālā a me ka hana like ʻole e hiki ai iā lākou ke lawelawe ma ke ʻano he mea hoʻoponopono i nā pane kelepona, me nā kuleana koʻikoʻi e like me:
Hui Pūʻulu:
Hoʻokumu ʻo Phospholipids i nā poloka kūkulu kumu o nā membrane cellular, e hoʻokumu ana i ke ʻano hana no ka hoʻokaʻawale ʻana o nā keʻena kelepona a me ka localization o nā protein hōʻailona. ʻO kā lākou hiki ke hoʻoulu i nā microdomains lipid, e like me nā lipid rafts, hoʻopili i ka hoʻonohonoho spatial o nā hōʻailona hōʻailona a me kā lākou mau pilina, e hoʻopili ana i ka kikoʻī a me ka pono.
Hoʻololi hōʻailona:
Hana ʻo Phospholipids ma ke ʻano he mau kikowaena nui i ka lawe ʻana i nā hōʻailona extracellular i loko o nā pane intracellular. Hoʻohana ʻia nā Phosphoinositides ma ke ʻano he molekala hōʻailona, e hoʻololi ana i nā hana o nā protein effector like ʻole, ʻoiai ʻo nā momona momona manuahi a me nā lysophospholipids e hana ma ke ʻano he mau ʻelele lua, e hoʻohuli ana i ka hoʻāla ʻana o nā cascades hōʻailona a me ka hōʻike gene.
Hoʻololi ʻana i ka hōʻailona kelepona:
Hāʻawi ka Phospholipids i ka hoʻoponopono ʻana i nā ala hōʻailona like ʻole, e hoʻohana ana i ka mana ma luna o nā kaʻina hana e like me ka hoʻonui ʻana o ka cell, ka ʻokoʻa, apoptosis, a me nā pane kūlohelohe. ʻO kā lākou komo ʻana i ka hoʻokumu ʻana o nā mea hoʻolaha lipid bioactive, me nā eicosanoids a me sphingolipids, e hōʻike hou ana i ko lākou hopena i nā pūnaewele hōʻailona inflammatory, metabolic, a apoptotic.
Ka launa pū waena:
Hoʻokomo pū ʻo Phospholipids i ka kamaʻilio intercellular ma o ka hoʻokuʻu ʻana i nā mediators lipid, e like me prostaglandins a me leukotrienes, ka mea e hoʻololi i nā hana o nā cell a me nā ʻiʻo e pili ana, e hoʻoponopono ana i ka mumū, ka ʻike ʻeha, a me ka hana vascular.
ʻO nā haʻawina multifaceted o phospholipids i ka hōʻailona cell a me ka kamaʻilio e hōʻike ana i ko lākou mea nui i ka mālama ʻana i ka homeostasis cellular a me ka hoʻonohonoho ʻana i nā pane physiological.
B. Nā kuhikuhi no ka wā e hiki mai ana no ka noiʻi ʻana i nā Phospholipids i ka hōʻailona kelepona
Ke hoʻomau nei ka wehe ʻia ʻana o nā hana koʻikoʻi o nā phospholipids i ka hōʻailona kelepona, ua puka mai kekahi mau ala hoihoi no ka noiʻi e hiki mai ana, e like me:
Nā Kūlana Kūwaena:
ʻO ka hoʻohui ʻana i nā ʻenehana analytical kiʻekiʻe, e like me ka lipidomics, me ka molecular a me ka cellular biology e hoʻonui i ko mākou ʻike i ka spatial and temporal dynamics o phospholipids i nā kaʻina hana hōʻailona. ʻO ka ʻimi ʻana i ka crosstalk ma waena o ka lipid metabolism, membrane trafficking, a me ka hōʻailona kelepona e wehe i nā mīkini hoʻoponopono hou a me nā pahuhopu therapeutic.
Nā Manaʻo Biology Pūnaehana:
ʻO ka hoʻohana ʻana i nā ʻōnaehana biology, me ka hoʻohālikelike makemakika a me ka nānā ʻana i ka pūnaewele, e hiki ai ke wehewehe i ka hopena honua o nā phospholipids ma nā pūnaewele hōʻailona kelepona. ʻO ka hoʻohālikelike ʻana i nā pilina ma waena o nā phospholipids, nā enzymes, a me nā mea hōʻailona hōʻailona e wehewehe i nā waiwai e kū mai ana a me nā ʻano pane e hoʻokele ana i ka hoʻoponopono ala ala.
Nā hopena lapaʻau:
ʻO ka noiʻi ʻana i ka dysregulation o nā phospholipids i nā maʻi, e like me ke kanesa, nā maʻi neurodegenerative, a me nā metabolic syndromes, hāʻawi i kahi manawa e hoʻomohala ai i nā lāʻau lapaʻau. ʻO ka hoʻomaopopo ʻana i nā kuleana o ka phospholipids i ka holomua ʻana o ka maʻi a me ka ʻike ʻana i nā hoʻolālā hou e hoʻololi i kā lākou mau hana e paʻa ana i ka ʻōlelo no nā ala lapaʻau pololei.
I ka hopena, ʻo ka hoʻonui mau ʻana o ka ʻike o nā phospholipids a me ko lākou komo ʻana i ka hōʻailona kelepona a me ke kamaʻilio e hōʻike ana i kahi palena hoihoi no ka hoʻomau ʻana i ka ʻimi a me ka hopena unuhi i nā ʻano ʻano noiʻi biomedical.
Kuhikuhi:
Balla, T. (2013). Phosphoinositides: nā lipid liʻiliʻi me ka hopena nui i ka hoʻoponopono cell. Nā Manaʻo Physiological, 93 (3), 1019-1137.
Di Paolo, G., & De Camilli, P. (2006). ʻO Phosphoinositides i ka hoʻoponopono cell a me ka dinamika membrane. Nature, 443(7112), 651-657.
Kooijman, EE, & Testerink, C. (2010). ʻO ka waikawa Phosphatidic: kahi mea pāʻani koʻikoʻi e puka mai ana i ka hōʻailona kelepona. Nā Kūlana i ka ʻepekema Mea kanu, 15(6), 213-220.
Hilgemann, DW, & Ball, R. (1996). Hoʻoponopono i ka naʻau Na (+), H (+) -exchange a me K (ATP) pālolo pālolo e PIP2. ʻEpekema, 273(5277), 956-959.
Kaksonen, M., & Roux, A. (2018). Mechanisms o ka endocytosis-mediated clathrin. Nature Reviews Molecular Cell Biology, 19(5), 313-326.
Balla, T. (2013). Phosphoinositides: nā lipid liʻiliʻi me ka hopena nui i ka hoʻoponopono cell. Nā Manaʻo Physiological, 93 (3), 1019-1137.
Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2014). Molecular Biology of the Cell (6th ed.). ʻEpekema Garland.
Simons, K., & Vaz, WL (2004). Nā ʻōnaehana hoʻohālike, nā lāʻau lipid, a me nā membrane cell. Nānā Makahiki o Biophysics a me Biomolecular Structure, 33, 269-295.
Ka manawa hoʻouna: Dec-29-2023
