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University of Groningen Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine Martines, Anne-Claire

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(1)University of Groningen. Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine Martines, Anne-Claire. IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.. Document Version Publisher's PDF, also known as Version of record. Publication date: 2019 Link to publication in University of Groningen/UMCG research database. Citation for published version (APA): Martines, A-C. (2019). Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine: from computational model to mice to man. Rijksuniversiteit Groningen.. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.. Download date: 28-06-2021.

(2) Chapter 7 General discussion.                       .

(3)

(4) ‡‡”ƒŽ†‹• —••‹‘

(5)  –Š‹• –Š‡•‹•ǡ

(6)  –‘‘ ƒ ›•–‡• ‡†‹ ‹‡ ƒ’’”‘ƒ Š –‘ ƒ††”‡•• –Š‡ “—‡•–‹‘ ™Šƒ– ‡Ž‹ ‹–• Š›’‘‡–‘–‹ Š›’‘‰Ž› ‡‹ƒ‹•‘‡†‡ˆ‹ ‹‡–•—„Œ‡ –•ƒ†™Šƒ–’”‘–‡ –•‘–Š‡”•ƒ‰ƒ‹•– –Š‹•Ǥ

(7) ‘”†‡”–‘†‘•‘

(8) ‡˜ƒŽ—ƒ–‡††‡ˆ‹ ‹‡ ›‹ƒ ‘’—–ƒ–‹‘ƒŽ‘†‡Žǡ‹‹ ‡‹˜‹˜‘ ƒ†‹Š—ƒ•‹˜‹–”‘Ǥ

(9) –Š‹• Šƒ’–‡”

(10) ™‹ŽŽˆ‹”•–†‹• —••–Š‡’”‡•‡–‡†’”‘Œ‡ –•ǡ–Š‡”‡•—Ž–•ǡ ‹’Ž‹ ƒ–‹‘•ǡˆ‘ŽŽ‘™Ǧ—’”‡ ‘‡†ƒ–‹‘•ƒ†ˆ—–—”‡’”‘•’‡ –•ǡˆ”‘ ‘’—–ƒ–‹‘ƒŽ‘†‡Ž–‘ ‹ ‡–‘ƒǤ ‹ƒŽŽ›ǡ

(11) ™‹ŽŽ‡†™‹–Š•‘‡‘˜‡”ƒ” Š‹‰ ‘ Ž—•‹‘•ˆ”‘–Š‹•–Š‡•‹•Ǥ . Navigating from computational metabolic model to mice to man Computational modeling of mFAO and beyond

(12) Chapter 2ǡ

(13) ‹˜‡•–‹‰ƒ–‡†–Š‡‘”‹‰‹‘ˆ–Š‡•–‡ƒ†›Ǧ•–ƒ–‡ˆŽ—šǦ†‡ Ž‹‡’Š‡‘‡‘‘„•‡”˜‡† ‹ –Š‡ ‘’—–ƒ–‹‘ƒŽ ‘†‡Ž ‘ˆ –Š‡ ‹•‘Žƒ–‡†   ’ƒ–Š™ƒ› ‹ ”ƒ– Ž‹˜‡”Ǥ

(14)  ƒ††‹–‹‘ǡ

(15)  ‹˜‡•–‹‰ƒ–‡† –Š‡ ”‘Ž‡ ‘ˆ ‡œ›‡ ’”‘‹• —‹–› ‹ ‹–Ǥ

(16)  ‹†‡–‹ˆ‹‡† –Šƒ– ‡œ›‡ ’”‘‹• —‹–› ‡•’‡ ‹ƒŽŽ›–Šƒ– ‘ˆ ǡ ’Žƒ›• ƒ ‹’‘”–ƒ– ”‘Ž‡ ‹ –Š‡ ˆŽ—š †‡ Ž‹‡Ǥ œ›‡ ’”‘‹• —‹–› Ž‡ƒ†•–‘‹Š‹„‹–‹‘‘ˆ‡–ƒ„‘Ž‹ ”‡ƒ –‹‘•„› ‘’‡–‹‰•—„•–”ƒ–‡•ǤŠ‹•‹Š‹„‹–‹‘ƒ’’‡ƒ”•–‘ ”‡•—Ž–‹ƒ•–”‘‰‹Š‹„‹–‹‘‘ˆ–Š‡ ˆŽ—šƒ– ›–‘•‘Ž‹ ’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘•Š‹‰Š‡” –Šƒƒ ‡”–ƒ‹–Š”‡•Š‘Ž†˜ƒŽ—‡Ǥ

(17) ’‘”–ƒ–Ž›ǡ ‘’‡–‹–‹˜‡‹Š‹„‹–‹‘ƒ†‡œ›‡’”‘‹• —‹–› ƒ”‡ ‹–”‹ ƒ–‡ ’”‘’‡”–‹‡• ‘ˆ ƒ–—”ƒŽ „‹‘Ž‘‰‹ ƒŽ ’”‘ ‡••‡•Ǥ

(18) – ‹• –Š—• ‹–‡”‡•–‹‰ –‘ ‘–‹ ‡ –Šƒ– ”‡ƒ –‹‘• ƒ”‡ƒ Š •—„•–ƒ–‹ƒŽŽ›Š‹‰Š‡” ”ƒ–‡• ‹ ‹•‘Žƒ–‹‘ǡ ™Š‡ ƒ Š‘‘‰‡‡‘—• •—„•–”ƒ–‡ ‹š–—”‡‹•’”‡•‡–‡†–‘–Š‡‡œ›‡ǡ–Šƒ™Š‡–Š‡‡œ›‡ǯ•’”‘’‡”–‹‡•ƒ”‡ Šƒ‰‡††—‡–‘ –Š‡ ’”‡•‡ ‡ ‘ˆ ‘’‡–‹‰ •—„•–”ƒ–‡• ‘” ‘–Š‡” ‘†‹ˆ‹‡”•Ǥ ‡”•‹•–‡– ‹„ƒŽƒ ‡• ‹ ”ƒ–‡• ™‹–Š‹ ƒ ‡–™‘” ‘—Ž† „‡ ‘‡ †‡–”‹‡–ƒŽ –‘ ‡–ƒ„‘Ž‹  Š‘‡‘•–ƒ•‹• ƒ† ƒ—•‡ –Š‡ †‡˜‡Ž‘’‡–‘ˆƒ’ƒ–Š‘Ž‘‰‹ •–ƒ–‡Ǥ

(19) ƒŽ•‘‹˜‡•–‹‰ƒ–‡†–Š‡•‡“—‡ ‡‘ˆ‡˜‡–•Ž‡ƒ†‹‰—’–‘–Š‡ Ž‘™ˆŽ—šƒ–Š‹‰Š’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘•Ǥ

(20) •Š‘™‡†–Šƒ–ƒ–Š‹‰Š ›–‘•‘Ž‹ ’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘•͸•—„•–”ƒ–‡‘ˆ•–ƒ”–‡†ƒ ——Žƒ–‹‰ •—„•–ƒ–‹ƒŽŽ›„‡ˆ‘”‡–Š‡‘–Š‡” ‹–‡”‡†‹ƒ–‡• ‘ˆ –Š‡ ’ƒ–Š™ƒ›Ǥ ’’ƒ”‡–Ž›ǡ  †‹† ‘– ‡‡– –Š‡ Š‹‰Š ”‡ƒ –‹‘ ”ƒ–‡• †‡ƒ†‡† „› –Š‡ Žƒ”‰‡ •—„•–”ƒ–‡ •—’’Ž›ǡ ’ƒ”–‹ —Žƒ”Ž› ™Š‡ ‹– ™ƒ• ‹Š‹„‹–‡† „› ƒŽŽ –Š‡ ‹–‡”‡†‹ƒ–‡ƒ ›ŽǦ‘‡•–‡”•Ǥ‘•‡“—‡–Ž›ǡƒ˜‹ ‹‘—• › Ž‡‘ˆ‹Š‹„‹–‹‘„›‹–•‘™•—„•–”ƒ–‡• ƒ†’”‘†— –•‘ —””‡†ǡ”‡•—Ž–‹‰ ‹ ‘  †‡’Ž‡–‹‘ ƒ†Ž‘™‡” •–‡ƒ†›Ǧ•–ƒ–‡ ˆŽ—š‡• ƒ– Š‹‰Š ›–‘•‘Ž‹ ’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘•Ǥ

(21) –‡”‡•–‹‰Ž›ǡ‰ƒ‹‡†’‘•‹–‹˜‡ˆŽ—š ‘–”‘Žƒ† ͳ‰ƒ‹‡†‡‰ƒ–‹˜‡ˆŽ—š ‘–”‘Žƒ–Š‹‰Š’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘•ȏͳȐǤ›’‹ ƒŽŽ›ǡ–Š‡ˆ‹”•– ‡œ›‡‹ƒ’ƒ–Š™ƒ›Ž‘•‡•ˆŽ—š ‘–”‘Ž™Š‡‹–••—„•–”ƒ–‡ ‘ ‡–”ƒ–‹‘‹ ”‡ƒ•‡•ƒ†–Š‡ ‡œ›‡ •–ƒ”–• –‘ •‡•‡ ‹Š‹„‹–‹‘ „› ‹–• ‘™ ’”‘†— –• ‘” †‘™•–”‡ƒ ‡–ƒ„‘Ž‹–‡•Ǥ Ž—š ‘–”‘Ž–Š‡•Š‹ˆ–•–‘‡œ›‡•ˆ—”–Š‡”†‘™•–”‡ƒȏʹȐǤŠ‡‡‰ƒ–‹˜‡ˆŽ—š ‘–”‘Ž‡š‡”–‡†„› ͳƒ–Š‹‰Š•—„•–”ƒ–‡ ‘ ‡–”ƒ–‹‘•†‹•–‹‰—‹•Š‡†–Š‡ ‘†‡Žˆ”‘‘–Š‡”’ƒ–Š™ƒ› •–”— –—”‡•Ǥ

(22) –Š‡‡š–•‡ –‹‘

(23) ™‹ŽŽ‡˜ƒŽ—ƒ–‡–Š‡‡ˆˆ‡ –•‘ˆ–ƒ ‹–ƒ••—’–‹‘•‹–Š‡‘†‡Žǡ –Š‡‹” ‘•‡“—‡ ‡•ˆ‘”–Š‡‘†‡Žƒ†ƒ’‘••‹„Ž‡™ƒ›–‘ ‹” —˜‡––Š‡Ǥ . Assumptions •’”‡˜‹‘—•Ž›‹†‹ ƒ–‡†ǡ–Š‡’—„Ž‹•Š‡†‘†‡Ž• ‘–ƒ‹•‡˜‡”ƒŽ‹’Ž‹‡†ƒ••—’–‹‘•–Šƒ–ƒ› „‡”‡Ž‡˜ƒ––‘’‘‹–‘—–‹–Š‡Ž‹‰Š–‘ˆ—•‹‰–Š‡•‡‘†‡Ž•–‘ƒ‡’”‡†‹ –‹‘•ƒ„‘—–Š‡ƒŽ–Š ƒ††‹•‡ƒ•‡Ǥ ‹”•–ǡ

(24) ™‹ŽŽ†‹• —••ƒ••—’–‹‘•‘–Š‡‹‡–‹ •‘ˆ–Š‡‡œ›ƒ–‹ ”‡ƒ –‹‘•ǡƒˆ–‡” ™Š‹ Š

(25) ™‹ŽŽ†‡ƒŽ™‹–Šƒ••—’–‹‘•™‹–Š”‡‰ƒ”†–‘–Š‡‡–ƒ„‘Ž‹–‡•Ǥ. ʹʹ͹. 7.

(26) Šƒ’–‡”ͽ œ›ƒ–‹  ”‡ƒ –‹‘• ’”‘ ‡‡† ‹ ƒ ‡”–ƒ‹ †‹”‡ –‹‘ ™Š‡ –Š‡ ȟ  ‹• •ƒŽŽ‡” –Šƒ œ‡”‘Ǥ ‘” ‡œ›ƒ–‹ ”‡ƒ –‹‘•–Š‡ ƒŽ†ƒ‡”‡Žƒ–‹‘•Š‹’†‡• ”‹„‡•–Š‡”‡Žƒ–‹‘•Š‹’„‡–™‡‡‡“‘ˆ–Š‡ ”‡ƒ –‹‘ƒ†–Š‡”‡ƒ –‹‘Ǧ‡ Šƒ‹•Ǧ•’‡ ‹ˆ‹ ‹‡–‹ ’ƒ”ƒ‡–‡”•Ǥƒ Š”‡ƒ –‹‘‡ Šƒ‹• ™‹–Š–™‘‘”‘”‡•—„•–”ƒ–‡•ƒ†’”‘†— –•ǡƒ›Šƒ˜‡–™‘‘”‘”‡ ƒŽ†ƒ‡”‡Žƒ–‹‘•ȏ͵ȐǤŠ‡   ‘†‡Ž ‹ ‹–• —””‡– ˆ‘” ‹• Žƒ”‰‡Ž› „ƒ•‡† ‘ ‘˜‡‹‡ ‡ ‹‡–‹ • ȏͶȐǤ Š‹• ™ƒ• ƒ ’”ƒ‰ƒ–‹  Š‘‹ ‡ǡ•‹ ‡‹‡–‹ ’ƒ”ƒ‡–‡”•–‘†‡• ”‹„‡‘”‡ ‘’Ž‡š‹‡–‹ ‡ Šƒ‹••ƒ”‡ • ƒ” ‡Ǥ ‘” ‡šƒ’Ž‡ǡ  ‡ƒ ‡– ƒŽǤ ‡š’‡”‹‡–ƒŽŽ› †‡–‡”‹‡† –Šƒ– –Š‡ ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡Ǧ ƒ–ƒŽ›œ‡† ”‡ƒ –‹‘ ’”‘ ‡‡†• ƒ ‘”†‹‰ –‘ Dz”†‡”‡†Ǧ‹Ǧ‹dz ‡ Šƒ‹• ȏͷȐǤ ‡‘ˆ–Š‡ ‘””‡•’‘†‹‰ ƒŽ†ƒ‡”‡Žƒ–‹‘•Š‹’•ȏ͵Ȑ‹• ݁. ିοீᇱబ ோ். ி஺஽ு. ൌ ‫ܭ‬௘௤ ൌ. ௘௡௢௬௟ି஼௢஺ మ ܸ௙ ‫ܭ‬௠ ‫ܭ‬ ή ௔௖௬௟ି஼௢஺ ή ௜ ி஺஽  ܸ௥ ‫ܭ‬ ‫ܭ‬௠ ௜.

(27)  –Š‡   ‘†‡Ž ‹– ™ƒ• ƒ••—‡† –Šƒ– –Š‡ ‡“ ‘ˆ –Š‡ †‡Š›†”‘‰‡ƒ•‡ ”‡ƒ –‹‘ ™ƒ• ‹†‡’‡†‡– ‘ˆ Šƒ‹ǦŽ‡‰–ŠǤ ‘”‡‘˜‡”ǡ ‹ –Š‡ ‘˜‡‹‡ ‡ ‹‡–‹ • ‫†ƒ ʹܪܦܣܨ݅ܭ‬ ‫݈ݕܿܽ݅ܭ‬Ϋ‫”— ‘ –‘ ‘† ܣ݋ܥ‬ǡ „—–  ‫݈ݕܿܽ݉ܭ †ƒ ʹܪܦܣܨ݉ܭ‬Ϋ‫‘†ܣ݋ܥ‬ǡ ”‡•—Ž–‹‰ ‹ –Š‡ ˆ‘ŽŽ‘™‹‰ ƒŽ†ƒ‡”‡Žƒ–‹‘ǣ ‫ܭ‬௘௤ ൌ. ி஺஽ு ௘௡௢௬௟ି஼௢஺ ܸ௙ ‫ܭ‬௠ ‫ܭ‬௠ మ ή ௔௖௬௟ି஼௢஺ ή ி஺஽  ܸ௥ ‫ܭ‬௠ ‫ܭ‬௠. Š‡“—‡•–‹‘ƒ”‹•‡•–‘™Šƒ–‡š–‡––Š‡•‡ƒ••—’–‹‘• Šƒ‰‡–Š‡ ‘ Ž—•‹‘•†”ƒ™ˆ”‘–Š‡ ‘†‡ŽǤŠ‡ˆ‹”•–ƒ••—’–‹‘–Šƒ––Š‡‡“‹• Šƒ‹ǦŽ‡‰–Š‹†‡’‡†‡–‹‰Š–„‡“—‡•–‹‘ƒ„Ž‡Ǥ •‹‰–Š‡‘Ž‹‡ ƒŽ —Žƒ–‘”‘ˆȟ Ͳǯƒ†‡“˜ƒŽ—‡•ȋ‡—‹Ž‹„”ƒ–‘”Ȍȏ͸Ȑ

(28)  ƒŽ —Žƒ–‡†–Šƒ––Š‡”ƒ–‹‘ ‘ˆ ‡“ ˜ƒŽ—‡• ‘ˆ ͳ͸Ǧƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ–‹‘ ‘˜‡” ͶǦƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ–‹‘ ™ƒ• Ž‡•• –ŠƒͲǤͲ͵͵Ǥ•›‡–ǡ‹–‹•‘– Ž‡ƒ”Š‘™™‡ŽŽƒ†™‹–Š™Šƒ–‡””‘”–Š‡’”‡†‹ –‹‘•™‡”‡ƒ†‡Ǥ Š‡ ‘””‡ –ǡŠ‘™‡˜‡”ǡ™‹–Š–Š‡•ƒ‡˜ƒŽ—‡•ˆ‘”–Š‡ǯ•–Š‡ˆ‘”™ƒ”†ƒš™‘—Ž†„‡Š‹‰Š‡” ”‡Žƒ–‹˜‡–‘–Š‡”‡˜‡”•‡ƒš™Š‡–Š‡ƒ ›ŽǦ‘ Šƒ‹‹••Š‘”–‡”Ǥ‘”‡‘˜‡”ǡ•‘‡†ƒ–ƒ™‡”‡ ƒ˜ƒ‹Žƒ„Ž‡ˆ‘”–Š‡‹ǯ•ȏͷȐǤ ‘”ƒ ›ŽǦ‘†‡Š›†”‘‰‡ƒ•‡ǡˆ‘”‹•–ƒ ‡ǡ–Š‡›†‹ˆˆ‡”‡†„›ƒˆƒ –‘” ‘ˆ Ͷ ˆ”‘ –Š‡ ‘””‡•’‘†‹‰ ǯ• ȏͷȐǤ Š‡

(29)  Œ—•– ”‡’Žƒ ‡ –Š‡ ‹ǯ• „› –Š‡ ǯ•

(30)  ™‘—Ž† ‡••‡–‹ƒŽŽ›‡‡†–‘‹–”‘†— ‡ƒ ‘””‡ –‹‘ˆƒ –‘”ȋȽȌ‹–Š‡ ƒŽ†ƒ‡‡“—ƒ–‹‘ǣ ‫ܭ‬௘௤ ൌ. ி஺஽ு ௘௡௢௬௟ି஼௢஺ ͳ ܸ௙ ‫ܭ‬௠ ‫ܭ‬௠ మ ή ή ௔௖௬௟ି஼௢஺ ή ி஺஽  ߙ ܸ௥ ‫ܭ‬௠ ‫ܭ‬௠. ‘”‡ •’‡ ‹ˆ‹ ƒŽŽ›ǡ ™‹–Š‘—– –Š‡ ‘””‡ –‹‘ ˆƒ –‘”ǡ –Š‡ ”ƒ–‹‘. ௏೑ ௏ೝ.  ‹• ͲǤ͵ͺ ˆ‘” –Š‡ ͶǦƒ ›ŽǦ‘. †‡Š›†”‘‰‡ƒ–‹‘”‡ƒ –‹‘ǡ‹ ‘–”ƒ•––‘ƒ˜ƒŽ—‡‘ˆͳǤͷʹ™Š‡–Š‡ ‘””‡ –‹‘ˆƒ –‘”‘ˆͶ™ƒ•  Ž—†‡†Ǥ

(31) ‘–Š‡”™‘”†•ǡ–Š‡‡•–‹ƒ–‹‘‘ˆ–Š‡”ƒ–‡ƒ–™Š‹ Š–Š‡”‡˜‡”•‡”‡ƒ –‹‘”—•‹‰Š– „‡ˆƒ”Ž‡••‹ ‘’ƒ”‹•‘™‹–Š–Š‡ˆ‘”™ƒ”†”‡ƒ –‹‘–Šƒ—•‡†‹–Š‡‘”‹‰‹ƒŽ ‘†‡ŽǤ‘ ‡˜ƒŽ—ƒ–‡ –Š‹• ’”‘’‡”Ž›ǡ Š‘™‡˜‡”ǡ –Š‡ ™Š‘Ž‡ Ǯ”†‡”‡† ‹ ‹ ‡“—ƒ–‹‘ǯ •Š‘—Ž† „‡ —•‡†Ǥ Š‡ †‡‘‹ƒ–‘”‘ˆ–Š‡Dz”†‡”‡†‹‹dz”ƒ–‡‡“—ƒ–‹‘ƒŽ•‘ ‘–ƒ‹•‹’ƒ”ƒ‡–‡”•ǤŠ‹•‡ƒ• –Šƒ––Š‡‹αƒ••—’–‹‘ƒˆˆ‡ –•–Š‡‘†‡Ž‡†”‡ƒ –‹‘”ƒ–‡‹‘”‡–Šƒ‘‡™ƒ›ȏ͵ǡ͹ȐǤ

(32)  –Š‡ ’—„Ž‹•Š‡†   ‘†‡Ž•ǡ ›–‘•‘Ž‹  ’ƒŽ‹–‘›ŽǦ‘ ™ƒ• –Š‡ •‘Ž‡ •—„•–”ƒ–‡ ƒ† ͳ ‘†‡Ž‡†ƒ•ƒ•–”‹ –Ž›ͳ͸Ǧ•’‡ ‹ˆ‹ ‡œ›‡ȏͺǡͻȐǤŠ‡™ƒ•’‡”ˆ‘”‡†‘–Š‡’—„Ž‹•Š‡† ”ƒ– ‘†‡Ž ‹– •Š‘™‡† –Šƒ– ͳ Šƒ† •—„•–ƒ–‹ƒŽ ˆŽ—š ‘–”‘Ž ‘˜‡” –Š‡ ‘’Ž‡–‡ ”ƒ‰‡ ‘ˆ ›–‘•‘Ž‹ ’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘•ȏͳȐǤŠ‡–Š‡ͳ͸Ǧ•’‡ ‹ˆ‹ ͳ™ƒ•”‡’Žƒ ‡†„›ƒ ͳ™‹–Šƒ„”‘ƒ†Ǧ•’‡ –”— Šƒ‹ǦŽ‡‰–Š•’‡ ‹ˆ‹ ‹–›™Š‹Ž‡‡‡’‹‰ƒŽŽ‘–Š‡”’ƒ”ƒ‡–‡”•–Š‡. ʹʹͺ.

(33) ‡‡”ƒŽ†‹• —••‹‘ •ƒ‡ǡ–Š‡•–”‘‰ˆŽ—š†‡ Ž‹‡ƒ–Š‹‰Š’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘•™ƒ•‘–’”‡•‡–ǡ‡˜‡™‹–Š ƒ–™‹ ‡ƒ•Š‹‰Šͳƒšȋ ‹‰—”‡ͳȌǤ J (μmol.min-1.gProtein-1). 14. Published rat model Rat model w. sens. CPT1. 12. Rat model w. sens. CPT1, 2x Vcpt1. 10 8. 6 4 2 0. 0. 50. 100. [Palmitoyl-CoA]CYT ;ʅDͿ. Figure 1. Computational rat dynamic model of isolated mFAO with C16-specific CPT1 (solid lines), with C16-C4 sensitive CPT1 (dashed lines) and with C16-C4 sensitive CPT1 at twice larger Vmax (short dashed lines)..  Ž–Š‘—‰Š –Š‡”‡ ƒ”‡ ‘ ͶǦͳͶ ƒ ›ŽǦ‘ •—„•–”ƒ–‡• ’”‡•‡– ‹ –Š‹••‹—Žƒ–‹‘ǡ –Š‡ ͳͶǦͳͶ ƒ ›ŽǦ ƒ”‹–‹‡’”‘†— –• ƒ„‡ˆ‘”‡†‹–Š‡‹–‘ Š‘†”‹ƒŽƒ–”‹šƒ†–”ƒ•’‘”–‡†‘—–„› Ǥ

(34) –Š‹•™ƒ›–Š‡•—„•–”ƒ–‡ƒ†’”‘†— –•’‡ ‹ˆ‹ ‹–›‘ˆͳ ƒ’Žƒ›ƒ”‘Ž‡‡˜‡‹–Š‡ ƒ„•‡ ‡‘ˆͶǦͳͶ•—„•–”ƒ–‡•ǤŠ‹•‹†‹ ƒ–‡•–Šƒ––Š‡ Šƒ‹ǦŽ‡‰–Š•’‡ ‹ˆ‹ ‹–›‘ˆͳŠƒ•ƒ •–”‘‰ ‡ˆˆ‡ – ‘ –Š‡   ˆŽ—šǡ ƒ† –Š‡”‡ˆ‘”‡ ™ƒ””ƒ–• ˆ—”–Š‡” •–—†›Ǥ ‘” ‹•–ƒ ‡ǡ ‹ –Š‡ ‡š–‡†‡†Š—ƒ‹œ‡† ‘†‡Ž ˆ‘”  †‡ˆ‹ ‹‡ › ȋChapter 5Ȍ ƒ ——Žƒ–‹‰ ‡†‹—Ǧ Šƒ‹ ƒ ›ŽǦ‘ƒ”‡–”ƒ•’‘”–‡†‘—–‘ˆ–Š‡‹–‘ Š‘†”‹ƒƒ•ˆ”‡‡ƒ ‹†•ǤŠ‡–Š‡•‡ƒ”‡”‡ƒ –‹˜ƒ–‡†–‘ ƒ ›ŽǦ‘ ‹ –Š‡ ›–‘•‘Ž ƒ† –”ƒ•‡•–‡”‹ˆ‹‡† –‘ ƒ ›ŽǦ ƒ”‹–‹‡ „› ͳǡ ‹–• Šƒ‹ǦŽ‡‰–Š •’‡ ‹ˆ‹ ‹–›„‡ ‘‡•‹’‘”–ƒ–Ǥ••Š‘™‹Chapter 5ǡƒ•–”‹‹‰†‹ˆˆ‡”‡ ‡™ƒ•‘„•‡”˜‡†‹ –Š‡ ”‘„—•–‡•• ‘ˆ –Š‡   ™Š‡ –Š‡ Šƒ‹ǦŽ‡‰–Š •’‡ ‹ˆ‹ ‹–› ‘ˆ ͳ ™ƒ• ”‡•–”‹ –‡† –‘ ’ƒŽ‹–‘›ŽǦ‘Ǥ  ••—’–‹‘• ™‡”‡ ƒŽ•‘ ƒ†‡ ƒ„‘—– –Š‡ „‘—†ƒ”› ‡–ƒ„‘Ž‹–‡• ‹ –Š‡ ‘†‡ŽǤ ‡‘˜ƒŽǡ ”‡‰‡‡”ƒ–‹‘ ‘” ”‡‘š‹†ƒ–‹‘ ‘ˆ •‡˜‡”ƒŽ ‘ˆ –Š‡•‡ ‘’‘—†• ™‡”‡ ”‡’”‡•‡–‡† „› ƒ Dz•‹dz ”‡ƒ –‹‘Ǥ Š‡ •‹ ”‡ƒ –‹‘• ™‡”‡ ‹–”‘†— ‡† •— Š –Šƒ– –Š‡› †‘ ‘– ‡š‡”– ƒ› ˆŽ—š ‘–”‘ŽǤ Š‡•‡ƒ”‡–Š‡”‡‘š‹†ƒ–‹‘‘ˆ ǡ ‘˜‡”•‹‘‘ˆƒ ‡–›ŽǦ‘„ƒ ‹–‘‘ ƒ†”‡‘š‹†ƒ–‹‘ ‘ˆ  ʹ –Šƒ– ™‡”‡ ‹ Ž—†‡† ƒ• ƒ†Š•‹ǡ ƒ ‡•‹ ƒ† ˆƒ†Š•‹ǡ ”‡•’‡ –‹˜‡Ž›Ǥ ‘™‡˜‡”ǡ ‘–”‘Ž‘ˆ–Š‡ˆŽ—š–Š”‘—‰Š–Š‡ „›‡š–‡”ƒŽ‡ˆˆ‡ –‘”•‹˜‹˜‘‹•‘–ƒ„•‡–ǤŠ‡–Š‡•‡ •‹ ”‡ƒ –‹‘• ™‘—Ž† „‡ ‘†‡ŽŽ‡† ‡š’Ž‹ ‹–Ž›ǡ –Š‡› ‹‰Š– •Šƒ”‡ ‹ –Š‡ –‘–ƒŽ ˆŽ—š ‘–”‘Ž †‡’‡†‹‰‘–Š‡‹”‹‡–‹ ’ƒ”ƒ‡–‡”•ƒ† ƒ–ƒŽ›–‹  ƒ’ƒ ‹–›ǤŠ‹•‹•ƒŽ•‘‹Ž‹‡™‹–Š–Š‡ˆŽ—š ‘–”‘Ž‡š‡”–‡†„› ‹Š—ƒ‘†‡ŽȋChapter 5ȌǤŠ—•ǡ–Š‡”‡•—Ž–•‹Chapter 2•Š‘—Ž† „‡‹–‡”’”‡–‡†ƒ•–Š‡‡œ›‡•ǯ•Šƒ”‡‘ˆ ‘–”‘Žˆ‘”–Š‡’ƒ”–‘ˆ–Š‡–‘–ƒŽˆŽ—š ‘–”‘Ž–Šƒ–”‡•‹†‡• ‹ –Š‡   ’ƒ–Š™ƒ› ‹–•‡ŽˆǤ  ›ŽǦ ƒ”‹–‹‡• ™‡”‡ ‘– ‡š’‘”–‡† ˆ”‘ –Š‡ ‡ŽŽ ‹ –Š‡ ‘†‡Ž ˜‡”•‹‘ —•‡† ‹ Chapter 2 ƒ† ƒ”‡ –Š‡”‡ˆ‘”‡ –‡ Š‹ ƒŽŽ› †‡ƒ†Ǧ‡† ‡–ƒ„‘Ž‹–‡•Ǥ Š‹• ”‡’”‡•‡–•–Š‡‡š’‡”‹‡–ƒŽ ‘†‹–‹‘•‘ˆ‹•‘Žƒ–‡†‹–‘ Š‘†”‹ƒ‹ƒ•ƒŽŽ”‡ƒ –‹‘˜‡••‡Žǡ ˆ‘”™Š‹ Š–Š‡‘†‡ŽŠƒ†„‡‡˜ƒŽ‹†ƒ–‡†ȏͳͲȐǤ

(35) ˜‹˜‘ǡŠ‘™‡˜‡”ǡƒ ›ŽǦ ƒ”‹–‹‡• ƒ„‡‡š’‘”–‡† ‘—– ‘ˆ –Š‡ Š‡’ƒ–‘ ›–‡Ǥ š’‘”– ‘ˆ ƒ ——Žƒ–‡† ƒ ›Ž ‡“—‹˜ƒŽ‡–• ‘—Ž† ”‡Ž‹‡˜‡ –Š‡ ‘†‡ŽŽ‡† •›•–‡ ˆ”‘ –Š‡ ‘•‡“—‡ ‡• ‘ˆ ‡š ‡••‹˜‡ •—„•–”ƒ–‡ •—’’Ž›Ǥ

(36) †‡‡†ǡ ‹–”‘†— –‹‘ ‘ˆ –Š‡ ‡š’‘”–‘ˆƒ ›ŽǦ ƒ”‹–‹‡•ǡ„›‡ƒ•‘ˆƒ††‹‰•‹’Ž‡ƒ••ƒ –‹‘‹‡–‹ •ȋ˜αͳͲǦ͸ȗȏǦƒ ›ŽǦ ƒ”‹–‹‡ȐȌǡŽƒ”‰‡Ž›”‡•‘Ž˜‡†–Š‡ˆŽ—šǦ†‡ Ž‹‡’Š‡‘‡‘ȋ ‹‰—”‡ʹȌǤ. ʹʹͻ. 7.

(37) Šƒ’–‡”ͽ. J (μmol.min-1.gProtein-1). 14. Published rat model model w. ac-carn export. 12. 10 8. 6 4 2 0. 0. 50. 100. [Palmitoyl-CoA]CYT ;ʅDͿ. Figure 2. Computational rat dynamic model of isolated mFAO with (dashed lines) and without (solid lines) cytosolic acyl-carnitine export.. ‹ƒŽŽ›ǡ ‹ –Š‡‘†‡Ž –Š‡ –ƒ ‹– ƒ••—’–‹‘ ‹•ƒ†‡ –Šƒ– Ǧ ƒ”‹–‹‡ ƒ‡˜‡” ‰‡– †‡’Ž‡–‡†Ǥ ‘™‡”’Žƒ•ƒǦ ƒ”‹–‹‡Ž‡˜‡Ž•Šƒ˜‡Š‘™‡˜‡”„‡‡”‡’‘”–‡†‹‹†‹˜‹†—ƒŽ•ȏͳͳȐǤŠ‹• ‹‰Š–„”‹‰ƒ„‘—–Ž‘™‡” ›–‘•‘Ž‹ Ǧ ƒ”‹–‹‡Ž‡˜‡Ž•Ǥ‹ ‡ ƒ”‹–‹‡‹•‹˜‘Ž˜‡†‹„‘–Š–Š‡ ͳƒ†ʹ ƒ–ƒŽ›œ‡†”‡ƒ –‹‘•ǡ Šƒ‰‡•‹ ƒ”‹–‹‡Ž‡˜‡Ž•‹‰Š–„‡Žƒ”‰‡‡‘—‰Š–‘Šƒ˜‡ ƒ‡ˆˆ‡ –‘–Š‡Ǧ ƒ–ƒŽ›œ‡†”‡ƒ –‹‘•Ǥ

(38) †‡‡†ǡƒ••Š‘™‹Chapter 5ǡŽ‘™‡”Ǧ ƒ”‹–‹‡ Ž‡˜‡Ž• Ž‹‹– –Š‡   ˆŽ—š •‡˜‡”‡Ž›Ǥ Š—• ‹ ”‡ƒŽ‹–›ǡ ›–‘•‘Ž‹  Ǧ ƒ”‹–‹‡ Ž‡˜‡Ž• ‘—Ž† „‡ ‘•‹†‡”‡†ƒ•’ƒ”–‘ˆƒ”‡‰—Žƒ–‘”›‡ Šƒ‹•–Šƒ–‡‡’•ͳǦ‡†‹ƒ–‡†‹’‘”–‘ˆ•—„•–”ƒ–‡ ‹–‘ –Š‡ ‹–‘ Š‘†”‹ƒ ƒ† ‘š‹†ƒ–‹‘ ‘ˆ –Š‹• •—„•–”ƒ–‡ ‹ „ƒŽƒ ‡Ǥ Š‡ –Š‡ ‹–‘ Š‘†”‹ƒŽ ‘š‹†ƒ–‹‘‹•‘—–‘ˆ„ƒŽƒ ‡™‹–Š–Š‡•—„•–”ƒ–‡‹’‘”–ǡ‹–‡”‡†‹ƒ–‡‡–ƒ„‘Ž‹–‡•ƒ ——Žƒ–‡ ƒ† ƒ „‡ ‡š ”‡–‡† ‹ –Š‡ —”‹‡ ƒ• –Š‡‹” ƒ”‹–‹‡ ‘—–‡”’ƒ”–•Ǥ ‘•‡“—‡–Ž›ǡ ƒ”‹–‹‡ ‘‹‡–‹‡•ƒ”‡ Ž‘•– ˆ”‘ –Š‡ ‡ŽŽǤ

(39) ˆ †‡ ‘˜‘ •›–Š‡•‹• ‘ˆǦ ƒ”‹–‹‡ ƒ‘– ‡‡’ —’ ™‹–Š –Š‡ ƒ‘—– ‘ˆ ƒ”‹–‹‡ǡ Ǧ ƒ”‹–‹‡ Ž‡˜‡Ž• ™‹ŽŽ †‡ ”‡ƒ•‡Ǥ ‘™‡” ›–‘•‘Ž‹  ƒ ›ŽǦ ƒ”‹–‹‡ Ž‡˜‡Ž• •—„•‡“—‡–Ž›‹Š‹„‹––Š‡”ƒ–‡‘ˆ–Š‡ͳǦ ƒ–ƒŽ›œ‡†”‡ƒ –‹‘ƒ†•—„•‡“—‡–Ž›–‡’‘”ƒ”‹Ž› †‡ ”‡ƒ•‡–Š‡•—’’Ž›‘ˆ•—„•–”ƒ–‡–‘–Š‡ ǤŠ‡ ’ƒ–Š™ƒ› ƒ‹–—”‡‡’—’™‹–Š –Š‡ •—„•–”ƒ–‡ •—’’Ž› ‘ˆ ͳǤ Š‡ “—‡•–‹‘ –‘ „‡ ƒ††”‡••‡† ‹• ‹ˆ –Š‹• ‡ Šƒ‹• ‹• “—ƒ–‹–ƒ–‹˜‡Ž› ƒ’ƒ„Ž‡‘ˆ’”‡˜‡–‹‰–Š‡ˆŽ—š†‡ Ž‹‡ǤƒŽ–‡”ƒ–‹˜‡• ‡ƒ”‹‘™‘—Ž†„‡–Šƒ– –Š‡ˆŽ—š†‡ Ž‹‡Šƒ’’‡•ǡ‘–„‡ ƒ—•‡‘ˆ‘ †‡’Ž‡–‹‘„—–„‡ ƒ—•‡ ƒ”‹–‹‡Ž‡˜‡Ž•ƒ”‡•‘ Ž‘™–Šƒ–ͳ‹••‡˜‡”‡Ž›•Ž‘™‡††‘™ǤŠ—•ǡ“—ƒ–‹–ƒ–‹˜‡ƒƒŽ›•‹•‘ˆ–Š‡ ƒ”‹–‹‡‡ ‘‘› ƒ›Šƒ˜‡ Ž‹‹ ƒŽ‹’‘”–ƒ ‡Ǥ  

(40) Chapter ͷ

(41) ‡š–‡†‡†–Š‡‘†‡Ž™‹–Šƒ•‡–‘ˆ‡œ›ƒ–‹ ”‡ƒ –‹‘™Š‹ Š ƒ’Žƒ›ƒ”‘Ž‡‹ •–ƒ„‹Ž‹œ‹‰–Š‡ Ǥ

(42) †‹†‘–›‡–•–—†›–Š‡‡ˆˆ‡ –•‘ˆ’‘•–Ǧ–”ƒ•Žƒ–‹‘ƒŽ‘†‹ˆ‹ ƒ–‹‘•ȋ•Ȍ ‘ ‡œ›‡ ’ƒ”ƒ‡–‡”•Ǥ ‘Ǧ‡œ›ƒ–‹  ƒ ›Žƒ–‹‘ ‘ˆ   ‡œ›‡• ‘ —”• ƒ• –Š‡ ‘•‡“—‡ ‡‘ˆ–Š‡˜‡”›Š‹‰Š ‘ ‡–”ƒ–‹‘•‘ˆƒ ›ŽǦ‘‡•–‡”•‹‹–‘ Š‘†”‹ƒ’ƒ”–‹ —Žƒ”Ž› †—”‹‰ †‡ˆ‹ ‹‡ ›Ǥ‡’‡†‹‰‘–Š‡‡–ƒ„‘Ž‹ †‡ˆ‡ –‡œ›‡•™‡”‡’ƒŽ‹–‘›Žƒ–‡†ȏͳʹȐǡ ƒ ‡–›Žƒ–‡†ǡ ƒŽ‘›Žƒ–‡†ǡ •— ‹›Žƒ–‡†ǡ ‰Ž—–ƒ”›Žƒ–‡†ǡ ‘” „—–›”›Žƒ–‡†  ȏͳ͵ǡͳͶȐǤ  Š‡ ‡ˆˆ‡ –•‘ ‡œ›‡ ‹‡–‹ • Šƒ• ‘– ›‡– „‡‡ •–—†‹‡† ‹ †‡–ƒ‹ŽǤ ‘™‡˜‡”ǡ ”‡ ‡–Ž› ƒ ›Žƒ–‹‘ †ƒ–ƒ„ƒ•‡• ȏͳʹǡͳ͵ȐŠƒ˜‡„‡‡‰‡‡”ƒ–‡†ƒ†–Š‡ ‘‰‘‹‰†‡˜‡Ž‘’‡–‘ˆ–‘‘Ž•–‘ ’”‡†‹ ––Š‡‡ˆˆ‡ –‘ˆ –Š‡•‡•‘‹‡–‹ ’”‘’‡”–‹‡•ȏͳͷȐǡ”‡•—Ž–‡†˜‡”›”‡ ‡–Ž›‹–Š‡‰‡‡”ƒ–‹‘‘ˆƒ†ƒ–ƒ„ƒ•‡ ™‹–Š†‹•‡ƒ•‡Ǧƒ••‘ ‹ƒ–‡†•ȏͳ͸ȐǤŠ‡•‡†‡˜‡Ž‘’‡–•ƒ›‹–Š‡‡ƒ”ˆ—–—”‡‘ˆˆ‡”‘”‡ ‹•‹‰Š–‹–‘–Š‡‡ˆˆ‡ –•‘ˆ•‘‡œ›‡‹‡–‹ ’”‘’‡”–‹‡•‹Š‡ƒŽ–Šƒ††‹•‡ƒ•‡Ǥ

(43) Šƒ˜‡ƒŽ•‘ ‘–›‡– ‘•‹†‡”‡†–Š‡”‘Ž‡‘ˆ Šƒ‡Ž‹‰ƒ†•—„‹–‘ Š‘†”‹ƒŽŽ‘ ƒŽ‹œƒ–‹‘‹–Š‡‘†‡ŽǤ• ‹†‹ ƒ–‡†‹Chapter 1 and 2ǡƒŽŽ–Š‡ ‡œ›‡•Šƒ˜‡„‡‡•Š‘™–‘ƒ••‘ ‹ƒ–‡–‘  •—’‡” ‘’Ž‡š‡•ƒ†Ȁ‘”‘–Š‡”‡œ›‡•ȋ‹ Ž—†‹‰‘’Ž‡š

(44) ǡ  ʹǡ ‹–”ƒ–‡•›–Šƒ•‡ǡ  ƒ†  Ȍ –Šƒ– ƒ ˆƒ ‹Ž‹–ƒ–‡ –Š‡ ”‡ƒ –‹‘• ‘ˆ –Š‡ ‘””‡•’‘†‹‰   ‡œ›‡•Ǥ

(45) ’‘”–ƒ–Ž›ǡ ‹– Šƒ• ƒŽ•‘ „‡‡ ”‡’‘”–‡† –Šƒ– ‡˜‡ ‹ ͷ͹Ȁ͸ ‹ ‡ǡ –Šƒ– Šƒ˜‡ ƒ —•–ƒ„Ž‡ ʹ͵Ͳ.

(46) ‡‡”ƒŽ†‹• —••‹‘ •—’‡” ‘’Ž‡šƒ••‡„Ž›ˆƒ –‘”ͳȋ

(47) ȌǡƒŽŽ•—’‡” ‘’Ž‡š‡•ƒ”‡ƒ–‡ƒ”‘”ƒŽŽ‡˜‡Ž• ƒ†ƒŽ•‘–Š‡”‡•’‹”ƒ•‘‡ȋ‹Ǥ‡ ‘’Ž‡–‡ƒ••‡„Ž›‘ˆ‘’Ž‡š

(48) ǡ

(49)

(50)

(51) ǡ

(52) ƒ†ȌŠƒ•„‡‡ˆ‘—†–‘ „‡ƒ–‘”ƒŽŽ‡˜‡Ž•‹–Š‡Ž‹˜‡”ǡƒŽ–Š‘—‰Š–Š‡”‡’‘”–‡†”‡•—Ž–•ƒ”‡‘– ‘•‹•–‡–ȏͳ͹Ȃʹ͵ȐǤŠ‹• •—‰‰‡•–• ‘†‹–‹‘Ǧ†‡’‡†‡† •—’‡” ‘’Ž‡š ˆ‘”ƒ–‹‘ ƒ† –Š‹• •Š‘—Ž† „‡ ‹˜‡•–‹‰ƒ–‡† ‹ Ǧ‹ ‡Ǥ . So, what can be done to improve our understanding of the model’s behavior and to improve the accuracy of our dynamic modeling predictions? Š‡ ƒ„‘˜‡ †‹• —••‹‘ •Š‘™‡† –Šƒ– –Š‡ ƒ••—’–‹‘• ƒˆˆ‡ – –Š‡ ’”‡†‹ –‹‘• ƒ†‡ ™‹–Š –Š‡ ‘†‡ŽǤ

(53) –‹• Ž‡ƒ”–Šƒ–‡š’‡”‹‡–ƒŽ†ƒ–ƒ‘‡œ›‡’ƒ”ƒ‡–‡”•ǡ™Š‡”‡ƒŽŽ–Š‡ƒ –—ƒŽ‹• ‹ Ž—†‡†ǡ ƒ† ‡–ƒ„‘Ž‹–‡ ‘ ‡–”ƒ–‹‘• ƒ”‡ ‡‡†‡†Ǥ ‡‡”ƒŽŽ›ǡ Ǧ‹ • –‡ Š‘Ž‘‰›ǡ ‹ Ž—†‹‰’”‘–‡‘‹ •ǡ‡–ƒ„‘Ž‘‹ •ƒ†Ž‹’‹†‘‹ •ƒ”‡’”‘‹•‹‰–‡ Š‘Ž‘‰‹‡•™Š‹ Š‹‰Š– Š‡Ž’ ”‡•‘Ž˜‡ •‘‡ ‘ˆ –Š‡ Žƒ  ‘ˆ ‡š’‡”‹‡–ƒŽ †ƒ–ƒǤ ‘” –Š‡ Š—ƒ‹œ‡† ‘†‡Žǡ Š—ƒ ’”‡ ‹•‹‘Ǧ —– Ž‹˜‡” •Ž‹ ‡• ƒ”‡ ƒ ’”‘‹•‹‰ ‡š’‡”‹‡–ƒŽ •›•–‡ –‘ ‹‹  Š—ƒ Ž‹˜‡” ȏʹͶȐǤ ‘ŽŽƒ„‘”ƒ–‹‘™‹–Š–Š‡Ž‹˜‡”–”ƒ•’Žƒ–ƒ–‹‘–‡ƒ‹–Š‡ ‘ˆˆ‡”•ƒ—‹“—‡‘’’‘”–—‹–›–‘ ‘„–ƒ‹–Š‡•‡†ƒ–ƒǤ

(54) –Š‹••‡ –‹‘

(55) ™‹ŽŽˆ—”–Š‡”‡š’Ž‹ ‹–Ž›‰‹˜‡•‘‡Ž‡••‘„˜‹‘—•‡šƒ’Ž‡•‘ˆ ™Šƒ– ƒ„‡†‘‡–‘‹’”‘˜‡‘—”—†‡”•–ƒ†‹‰‘ˆ–Š‡‘†‡Žǯ•„‡Šƒ˜‹‘”ƒ†–Š‡ƒ —”ƒ ›‘ˆ –Š‡‘†‡Ž’”‡†‹ –‹‘•Ǥ

(56) ˆ–Š‡‡š’‡”‹‡–ƒŽŽ›Ǧ†‡–‡”‹‡†”‡ƒ –‹‘‡ Šƒ‹•‘ˆƒ”‡ƒ –‹‘‹• Š‘•‡ ˆ‘” —•‡ ‹ –Š‡ †›ƒ‹ ‘†‡Žǡ –Š‡ –Š‡ ‘””‡•’‘†‹‰ ƒŽ†ƒ‡”‡Žƒ–‹‘•Š‹’ ƒ „‡ —•‡†–‘‡•–‹ƒ–‡‹••‹‰’”‘†— –ǯ•ƒ†‹ǯ•Ǥ ‘”‡šƒ’Ž‡ǡˆ‘”–Š‡ƒ ›ŽǦ‘†‡Š›†”‘‰‡ƒ•‡ ”‡ƒ –‹‘ǡ–Š‡ˆȀ””ƒ–‹‘‹•‡š’‡ –‡†–‘„‡͵Ǥͷƒ†͹Ǥͷȏ͹ǡʹͷȐƒ†–Š‡ Šƒ‹ǦŽ‡‰–ŠǦ•’‡ ‹ˆ‹ ‡“ „‡–™‡‡͸ƒ†ͳͺͲȏ͸ǡ͹ǡʹͷȐǤŠ‡–Š‡‹ƒ†˜ƒŽ—‡•ˆ‘” ƒ†  ʹƒ”‡‡’––Š‡•ƒ‡ ƒ•‹–Š‡‘”‹‰‹ƒŽ‘†‡Žȋ˜ƒŽ—‡•‘”‹‰‹ƒ–‹‰ˆ”‘ȏ͹ǡʹ͸ȐȌǡ–Š‡‡‘›ŽǦ‘ǯ• ƒ„‡‡•–‹ƒ–‡†Ǥ

(57) – ƒ•—„•‡“—‡–Ž›„‡†‡–‡”‹‡†™Š‡–Š‡”—•‹‰–Š‡ ƒŽ†ƒ‡”‡Žƒ–‹‘•Š‹’‹–Š‹•™ƒ›ˆ‘”–Š‡ ‡œ›‡•‹–Š‡‘†‡ŽŠƒ•ƒ‡ˆˆ‡ –‘–Š‡‘†‡Ž„‡Šƒ˜‹‘”Ǥ ‹ƒŽŽ›ǡ’‡”–ƒ‹‹‰–‘‡š’‡”‹‡–ƒŽ˜ƒŽ‹†ƒ–‹‘‘ˆ†›ƒ‹ ‡–ƒ„‘Ž‹ ‘†‡Ž‹‰ǡ’”‡ˆ‡”‡ ‡ ƒ „‡‰‹˜‡–‘”‡•—Ž–•‹–Š‡ˆ‹”•–‹—–‡•‘”Š‘—”‘ˆ–Š‡•‹—Žƒ–‹‘Ǥ‡›‘†–Š‹•ǡ‡•’‡ ‹ƒŽŽ›‹ ‡–ƒ„‘Ž‹•ǡ–Š‡‘„–ƒ‹‡†•‹—Žƒ–‹‘”‡•—Ž–•‹‰Š–„‡ ‘‡‘”‡ƒ†‘”‡—”‡Ž‹ƒ„Ž‡ǤŠ‹•‹• „‡ ƒ—•‡‹‡–ƒ„‘Ž‹•ǡ’”‘ ‡••‡•Ȃ™‹–Š‡š ‡’–‹‘•Ȃ ƒŠƒ”†Ž›„‡ ‘•‹†‡”‡†–‘ƒ””‹˜‡ƒ–ƒ •–‡ƒ†› •–ƒ–‡Ǥ ‡–ƒ„‘Ž‹  ’ƒ–Š™ƒ›• ƒ”‡ ‹–”‹ ƒ–‡Ž› ‹–‡” ‘‡ –‡†ǡ ‡š– –‘ –Š‡ •™‹ˆ– ƒ† •—„•–ƒ–‹ƒŽ ‡ˆˆ‡ – –Šƒ– ‡˜‹”‘‡–ƒŽ ‘†‹ˆ‹‡”• ‘—Ž† Šƒ˜‡ ‘ –Š‡ ˆ— –‹‘‹‰ ‘ˆ –Š‡•‡ ’ƒ–Š™ƒ›•Ǥ

(58) –‹• ‘•‡“—‡–Ž›—†‡”•–ƒ†ƒ„Ž‡–Šƒ–‹‡š’‡”‹‡–•’‡”–ƒ‹‹‰–‘‡–ƒ„‘Ž‹• “—‹ ƒ –‹‘‹•–ƒ‡–‘“—‡ Š”‡ƒ –‹‘‹š–—”‡•‘”ˆ”‡‡œ‡Ǧ Žƒ’‘”‰ƒ•–‘Ž‘ ƒ‡–ƒ„‘Ž‹  •–ƒ–‡—–‹Ž•ƒ’Ž‡ƒƒŽ›•‹•ǤŠ‡‘†‡Ž‹‰ƒ‡–ƒ„‘Ž‹ ’ƒ–Š™ƒ›‹ƒ†›ƒ‹ ‘†‡Žǡ™Š‡”‡ –Š‹• ’ƒ–Š™ƒ› ‹• ‘ˆ–‡ Žƒ”‰‡Ž› ‹•‘Žƒ–‡†ǡ ‹– ƒ –ƒ‡ Š‘—”• „‡ˆ‘”‡ ”‡ƒ Š‹‰ ƒ •–‡ƒ†›Ǧ•–ƒ–‡Ǥ ƒŽ‹†ƒ–‹‘‘ˆ•–‡ƒ†›•–ƒ–‡•‘ˆ•— Šƒ‘†‡Ž‹‰Š–ƒŽ•‘„‡‡••‡–‹ƒŽŽ›—ƒ––ƒ‹ƒ„Ž‡Ǥ—„•–”ƒ–‡ ‘ ‡–”ƒ–‹‘• ƒ† –Šƒ– ‘ˆ ‘–Š‡” ‡–ƒ„‘Ž‹–‡• ƒ† ’ƒ”ƒ‡–‡”• –Šƒ– Šƒ˜‡ „‡‡ ˆ‹š‡† ‹ –Š‡ ‘†‡Ž ™‘—Ž† ƒŽ•‘ Šƒ˜‡ –‘ „‡ ƒ‹–ƒ‹‡† ‘•–ƒ– ‹ ˜‹–”‘ ‘” ‹ ˜‹˜‘Ǥ ‰‹‡‡”‹‰ ‘ˆ ‡š’‡”‹‡–ƒŽ•‡–—’•™‘—Ž†„‡”‡“—‹”‡†ǡŽ‹‡—•‹‰ ‘–‹—‘—••–‹””‡†Ǧ–ƒ”‡ƒ –‘”•ȋ

(59) •Ȍ ƒ†ƒŽƒ”‰‡ƒ‘—–‘ˆŽ‹˜‹‰ƒ–‡”‹ƒŽˆ‘”ƒŽƒ”‰‡”ƒ‰‡‘ˆ ‘†‹–‹‘•™‘—Ž†„‡‡‡†‡†ˆ‘”–Š‡ ‹–‡†‡† ˜ƒŽ‹†ƒ–‹‘Ǥ

(60)  ƒ•‡ ‘ˆ ‹•‘Žƒ–‡† ‹–‘ Š‘†”‹ƒ ˆ‘” ‹•–ƒ ‡ǡ •—„•–ƒ–‹ƒŽ ˆ— –‹‘ƒŽ †‡–‡”‹‘”ƒ–‹‘ ƒ„‡‡š’‡ –‡†„‡ˆ‘”‡–Š‡”‡“—‹”‡†–‹‡’‡”‹‘†‡ ‡••ƒ”›–‘ƒ‡˜ƒŽ‹†ƒ–‹‘ ‘ˆ •–‡ƒ†›Ǧ•–ƒ–‡ ”‡•—Ž–• ’‘••‹„Ž‡Ǥ ‘ ˜ƒŽ‹†ƒ–‡ •’‡ ‹ˆ‹  •–‡ƒ†›Ǧ•–ƒ–‡ ‘†‡Ž „‡Šƒ˜‹‘”•ǡ ƒ Žƒ”‰‡ —„‡”‘ˆ•—„•–”ƒ–‡ ‘ ‡–”ƒ–‹‘•‡‡†–‘„‡–‡•–‡†‹ƒŽ‹˜‹‰•›•–‡ǡ‘–‘Ž›–‘‘„–ƒ‹ –Š‡‡ ‡••ƒ”›ƒ‘—–‘ˆ ‘†‹–‹‘•–‘ƒ‡‹–’‘••‹„Ž‡˜ƒŽ‹†ƒ–‡•–‡ƒ†›Ǧ•–ƒ–‡‹•‹Ž‹ ‘”‡•—Ž–•ǡ ʹ͵ͳ. 7.

(61) Šƒ’–‡”ͽ „—–ƒŽ•‘†—‡–‘— ‡”–ƒ‹–‹‡•‹‡š’‡”‹‡–•ƒ†‹•‹Ž‹ ‘ȋƒ•‹†‹ ƒ–‡†ƒ„‘˜‡ȌǤŠ‡”‡ˆ‘”‡ǡ‹– ‘—Ž†„‡‘”‡”‡ƒŽ‹•–‹ –‘•‹—Žƒ–‡ ‘†‹–‹‘•–Šƒ–ƒ”‡’‘••‹„Ž‡‘” Ž‘•‡–‘’‘••‹„Ž‡‹Ž‹˜‹‰ •›•–‡•Ǥ ‡”‡‹ǡ‹–•Š‘—Ž†ƒŽ•‘„‡ ‘•‹†‡”‡†™Šƒ–‡ˆˆ‡ –•‡š–‡”ƒŽ’ƒ”ƒ‡–‡”•Šƒ˜‡‘–Š‡ ”‡ƒ†‘—–•–Šƒ–ƒ”‡‹–‡†‡†–‘˜ƒŽ‹†ƒ–‡–Š‡‹Ǧ•‹Ž‹ ‘”‡•—Ž–•Ǥ. Mouse models as tools to understand symptomatology in MCADD

(62) Chapter 3ǡ

(63) ‹˜‡•–‹‰ƒ–‡†™Š‹ Š‡–ƒ„‘Ž‹ ’ƒ–Š™ƒ›• ‘–”‹„—–‡–‘–Š‡”‘„—•–‡••‘ˆǦ  ‹ ‡ —†‡” ˆ‡† ƒ† ˆƒ•–‹‰ ‘†‹–‹‘• ‘ ƒ Š‹‰ŠǦ ‘” Ž‘™Ǧˆƒ– †‹‡–Ǥ ‘—” –”ƒ• ”‹’–• ‘ˆ ‡–ƒ„‘Ž‹  ƒ –‹˜‡ ‡œ›‡• ™‡”‡ †‹ˆˆ‡”‡–‹ƒŽŽ› ‡š’”‡••‡†Ǥ ‘–ƒ„Ž›ǡ –™‘ ‘ˆ –Š‡ Ͷ –”ƒ• ”‹’–• ™‡”‡ˆ”‘‰‡‡•‡ ‘†‹‰ˆ‘”‡œ›‡•–Šƒ– ƒ–ƒŽ›œ‡‘ǦƒȋȌȋ ȌǦ‹˜‘Ž˜‹‰”‡ƒ –‹‘•Ǥ

(64)  ƒ††‹–‹‘ǡ „› ‡ƒ• ‘ˆ ‰‡‡Ǧ•‡–Ǧ‡”‹ Š‡– ƒƒŽ›•‡•ǡ

(65)  •Š‘™‡† –Šƒ– ‰‡‡• ‘†‹‰ ˆ‘” ‡œ›‡• –Šƒ– ƒ–ƒŽ›œ‡ ‘Ǧ ƒ ȋȌȋ ȌǦ‹˜‘Ž˜‹‰ ”‡ƒ –‹‘• ƒ”‡ ƒŽ–‡”‡† ‹ ‡š’”‡••‹‘ „‡–™‡‡  ƒ†  ‹ ‡Ǥ Š‹• ‹• ‹ Ž‹‡ ™‹–Š ƒ ‹’‘”–ƒ– ”‘Ž‡ ‘ˆ „‘–Š ‘ˆƒ –‘”• ‹ –Š‡ ‘’—–ƒ–‹‘ƒŽ‘†‡Ž‘ˆ‹•‘Žƒ–‡†”ƒ– ȋChapter 2Ȍƒ†‘ˆ‘‹–Š‡ǦŠ—ƒ ‘’—–ƒ–‹‘ƒŽ ‘†‡Ž ‘–ƒ‹‹‰ –Š‡ ‘”‡ ͳ͸Ǧ•’‡ ‹ˆ‹  ͳ ‡œ›‡ ȋChapter 5ȌǤ —” ‡š’‡”‹‡–ƒŽ”‡•—Ž–ˆ”‘–Š‹••–—†›ƒ”‡”‡Ž‡˜ƒ–‹–Š‡ ‘–‡š–‘ˆ–Š‡DzdzŠ›’‘–Š‡•‹•„› ‹– Š‡ŽŽ ‡– ƒŽǤ ȏʹ͹ǡʹͺȐǤ Š‹• Š›’‘–Š‡•‹• ’”‡†‹ –• –Šƒ– ‘  •‡“—‡•–”ƒ–‹‘ǡ –‘š‹ ‹–› ‘” ”‡†‹•–”‹„—–‹‘ȋŠ‡ ‡Ȍ™‘—Ž†‘ —”‹ƒ›‘ˆ‹’ƒ‹”‡–•‹‘‡•–‡”†‡‰”ƒ†ƒ–‹‘ ’ƒ–Š™ƒ›•ǡ‹ Ž—†‹‰ †‡ˆ‹ ‹‡ ‹‡•Ǥ

(66) –Šƒ•„‡‡’”‘’‘•‡†ȏʹ͹ǡʹͺȐ–Šƒ–ƒ›‘ˆ–Š‡–›’‹ ƒŽ •›’–‘• ’”‡•‡–‹‰ ‹ –Š‡•‡ ƒ•‡•ǡ •— Š ƒ• Š›’‘‰Ž› ‡‹ƒǡ ƒ”‡ ƒ ”‡•—Ž– ‘ˆ –Š‹•  ’Š‡‘‡‘Ǥ

(67)  ƒŽ•‘ ‘„•‡”˜‡† ƒ †‘™”‡‰—Žƒ–‹‘ ‹ ‰‡‡• ‹˜‘Ž˜‡† ‹ †‡–‘š‹ˆ‹ ƒ–‹‘ ‡ Šƒ‹••Ǥ

(68)  Ž‹‡ ™‹–Š –Š‹•ǡ Š‡’ƒ–‘Š‹•–‘Ž‘‰‹ ƒŽ ƒƒŽ›•‹• •Š‘™‡† ƒ –”‡† –‘™ƒ”†• ‹ˆŽƒƒ–‹‘‹–Š‡Ž‹˜‡”‘ˆǦ‹ ‡Ǥ

(69) –‡”‡•–‹‰Ž›ǡ‹Ǧ‘—•‡™‹–Š–Š‡‘•– •‡˜‡”‡‡–ƒ„‘Ž‹ ’Š‡‘–›’‡ƒˆ–‡” ‘Ž†‡š’‘•—”‡ȋChapter 4ȌǡƒŽ•‘•‡˜‡”‡•–‡ƒ–‘Š‡’ƒ–‹–‹•™ƒ• ‘„•‡”˜‡†ǤŠ‹•‹‰Š–’‘‹––‘’”‘‰”‡••‹‘‘ˆ–Š‡Ǧ’Š‡‘–›’‡—’‘•™‹– Š‹‰ˆ”‘ ‡š’‘•—”‡ –‘ ƒ ‹Ž† ‘†‹–‹‘ –‘ ƒ ‘†‹–‹‘ ‘ˆ Š‹‰ŠǦ‡‡”‰› †‡ƒ†Ǥ Š‡ ‘„•‡”˜‡† Ž‹˜‡” ‹ˆŽƒƒ–‹‘‹‰Š–„‡ƒ••‘ ‹ƒ–‡†™‹–Šƒ ——Žƒ–‡†ǡƒ•™ƒ•”‡’‘”–‡†‹Š—ƒ –‹••—‡•ȏʹͻǡ͵ͲȐǤ

(70) –‹•ƒŽ•‘’‘••‹„Ž‡–Šƒ––Š‡”‘„—•–‡••‹Ǧ‹ ‡‹•’ƒ”–Ž›‡†‹ƒ–‡†„› ƒƒ†ƒ’–ƒ–‹‘‹Š‡’ƒ–‹ ‹–‘ Š‘†”‹ƒŽ ‘–‡–ǤƒŽ›•‹•‘ˆŽ‹’‹†Ǧƒ†’”‘–‡‹‘š‹†ƒ–‹‘ƒ† ’‘–‡–‹ƒŽƒ†ƒ’–ƒ–‹‘„›‹ ”‡ƒ•‡†‹–‘ Š‘†”‹ƒŽ ‘–‡–‹–Š‡ͳ͸ǦŠ‘—”ˆƒ•–‡†‹ ‡ȋChapter 3Ȍƒ”‡—†‡”™ƒ›Ǥ

(71) Chapter 4ǡ™Š‡”‡Ǧ‹ ‡™‡”‡ˆƒ•–‡†ƒ†•—„•‡“—‡–Ž› ‘Ž†Ǧ‡š’‘•‡†ǡ

(72) ‘„–ƒ‹‡† –Š”‡‡‘–Š‡”‹–‡”‡•–‹‰”‡•—Ž–•Ǥ ‹”•–Ž›ǡ

(73) •Š‘™‡† ˆ‘”–Š‡ˆ‹”•– –‹‡ –Šƒ– Ǧ‹ ‡Šƒ† •‹‰‹ˆ‹ ƒ–Ž›Ž‘™‡”„Ž‘‘†‰Ž— ‘•‡Ž‡˜‡Ž•ƒ––‡”‹ƒ–‹‘–Šƒ‹ ‡Ǥ

(74) ƒ††‹–‹‘ǡ–Š‡‘—•‡ ™‹–Š –Š‡ ‘•– •‡˜‡”‡ ’Š‡‘–›’‡ǡ •Š‘™‡† „‘–Š •‡˜‡”‡ •–‡ƒ–‘Š‡’ƒ–‹–‹• ƒ† „Ž‘‘† ‰Ž— ‘•‡ †‡ ”‡ƒ•‡†—”‹‰ ‘Ž†‡š’‘•—”‡ǡƒ•‘’’‘•‡†–‘–Š‡‰‡‡”ƒŽ„Ž‘‘†‰Ž— ‘•‡‹ ”‡ƒ•‡‘„•‡”˜‡†‹ „‘–Šƒ†‹ ‡†—”‹‰ ‘Ž†‡š’‘•—”‡Ǥ‹–Š–Š‹•

(75) Šƒ˜‡ ‘ˆ‹”‡†–Šƒ––Š‡Ǧ ‘—•‡ ‘†‡Žǡ —†‡” •’‡ ‹ˆ‹  ‘†‹–‹‘•ǡ ‘—Ž† „‡ ‘•‹†‡”‡† ƒ ‰‘‘† ‘†‡Ž ˆ‘”  †‡ˆ‹ ‹‡ ›‹Š—ƒ•Ǥ‡ ‘†Ž›ǡ

(76) ‘„•‡”˜‡†ƒ ‘„‹ƒ–‹‘‘ˆ•‹‰‹ˆ‹ ƒ–Ž›Š‹‰Š‡”„Ž‘‘†ƒ ›ŽǦ ƒ”‹–‹‡ Ž‡˜‡Ž•ǡ •‹‹Žƒ” Š‡’ƒ–‹  ƒ ›ŽǦ ƒ”‹–‹‡ Ž‡˜‡Ž• ƒ† Š‹‰Š‡” Š‡’ƒ–‹  Ž‡˜‡Ž• ‘ˆ ‡†‹—Ǧ Šƒ‹ Ž‡˜‡Ž•‹Ǧ ‘’ƒ”‡†–‘‹ ‡ǤŠ‡ˆ‹†‹‰–Šƒ– ‘Ž†Ǧ‡š’‘•—”‡Ǧ‹†— ‡• ƒ ›ŽǦ ƒ”‹–‹‡ ‡š’‘”– ‘—– ‘ˆ –Š‡ Ž‹˜‡” ȏ͵ͳǡ͵ʹȐ –‘‰‡–Š‡” ™‹–Š ‹ ‘”’‘”ƒ–‹‘ ‘ˆ ƒ ——Žƒ–‡† ‡†‹—Ǧ Šƒ‹ ƒ ›ŽǦ‘ ‡•–‡”• ‹–‘  • ‹‰Š– Š‡Ž’ ’”‘–‡ – Ǧ ‹ ‡ ƒ‰ƒ‹•– •‡˜‡”‡ Ž‹˜‡”†ƒƒ‰‡ǤŠ‹”†Ž›ǡ

(77) ‘„•‡”˜‡†Ž‘™‡”Š‡’ƒ–‹ ƒ‹‘ƒ ‹†Ž‡˜‡Ž•ǡ„—–•‹‹Žƒ”„Ž‘‘†ƒ‹‘ ƒ ‹†Ž‡˜‡Ž•‹Ǧ ‘’ƒ”‡†–‘‹ ‡Ǥ•‹†‹ ƒ–‡†‹Chapter 4ǡ–Š‡Š‡’ƒ–‹ ƒ‹‘ ʹ͵ʹ.

(78) ‡‡”ƒŽ†‹• —••‹‘ ƒ ‹†•‹‰Š–Šƒ˜‡„‡‡—•‡†ƒ•ƒŽ–‡”ƒ–‹˜‡ˆ—‡Ž„›–Š‡Ž‹˜‡”ǡ„—–‘––‘ƒ‡š–‡––Šƒ–‹–™‘—Ž† ƒˆˆ‡ –„Ž‘‘†Ž‡˜‡Ž•Ǥ‡ƒ›™‘†‡”ǡŠ‘™‡˜‡”ǡ™Š‡–Š‡”‘–Š‡”‘”‰ƒ•–Šƒ–†‡’‡†‘ ǡ ™‘—Ž†ƒŽ•‘—•‡‘”‡ƒ‹‘ƒ ‹†•ƒ†™Š›–Š‹•†‘‡•‘–ƒˆˆ‡ ––Š‡„Ž‘‘† ‘ ‡–”ƒ–‹‘•Ǥ

(79) – ™‘—Ž† –Š‡”‡ˆ‘”‡ „‡ ‹–‡”‡•–‹‰ –‘ ‡ƒ•—”‡ ƒ‹‘ ƒ ‹†• ‹ ‘–Š‡” –‹••—‡• ƒ† ’‘••‹„Ž› ƒŽ•‘ •–—†›–Š‡–—”‘˜‡”‘ˆƒ‹‘ƒ ‹†•™‹–Š•–ƒ„Ž‡‹•‘–‘’‡•ȏ͵͵ȐǤŠ‹•‹‰Š–‰‹˜‡ƒ‹†‹ ƒ–‹‘‹ˆ –Š‡•›•–‡‹ ƒ‹‘Ǧƒ ‹†Š‘‡‘•–ƒ•‹•†‡’‡†•‘Š‹††‡”‡‰—Žƒ–‹‘Ǥ . /ŶǀŝƚƌŽ cell models of human MCADD

(80) Chapter 6ǡ

(81) ’”‡•‡–‡†ƒ•Š‘”–•–—†›ǡ™Š‡”‡–Š‡Ž‡˜‡Ž•‘ˆƒ ›ŽǦ ƒ”‹–‹‡ƒ†•‡Ž‡ ––ƒ”‰‡–‡† ‹–‘ Š‘†”‹ƒŽ ’”‘–‡‹• ‘ˆ –Š‡ ‡‡”‰› ‡–ƒ„‘Ž‹• ™‡”‡ †‡–‡”‹‡† ‹ —Ž–—”‡† •‹ ˆ‹„”‘„Žƒ•–•‘ˆ•›’–‘ƒ–‹ ƒ†ƒ•›–‘ƒ–‹ ‹†‹˜‹†—ƒŽ• ‘–”‘Ž•ǤŠ‡ˆ‹„”‘„Žƒ•–•‘ˆ –Š‡‡Ž†‡•–ǡƒ•›’–‘ƒ–‹ ‹†‹˜‹†—ƒŽ•Š‘™‡††‹ˆˆ‡”‡ ‡•™‹–Š–Š‡‘–Š‡”ƒ† Š‡ƒŽ–Š› ‘–”‘Žˆ‹„”‘„Žƒ•–ǡ•—‰‰‡•–‹‰‡–ƒ„‘Ž‹ ƒ†ƒ’–ƒ–‹‘•–Šƒ–ƒ›”‡Žƒ–‡–‘–Š‡ƒ„•‡ ‡‘ˆ •›’–‘•Ǥ‡š––‘–Š‹•ǡ‘–Š‡” ‡ŽŽ–›’‡• ‘—Ž†„‡—•‡†–‘•–—†›‡ Šƒ‹••—†‡”Ž›‹‰–Š‡ ˜ƒ”‹‘—• ’Š‡‘–›’‡• ‹  ‹†‹˜‹†—ƒŽ•Ǥ ”‘‹•‹‰ ‡ŽŽ –›’‡• ‹ Ž—†‡ ’ƒ–‹‡–Ǧ†‡”‹˜‡† ‹†— ‡†’Ž—”‹’‘–‡–•–‡ȋ‹Ȍ ‡ŽŽ•™Š‹ Š ƒ„‡†‹ˆˆ‡”‡–‹ƒ–‡†‹–‘Š‡’ƒ–‘ ›–‡•ȏ͵ͶȂ͵ͻȐǤ

(82) – ™‹ŽŽ„‡ ŠƒŽŽ‡‰‹‰–‘†‡˜‡Ž‘’–Š‹•‹–‘ƒ•›•–‡–Šƒ–•Š‘™•ƒ’ƒ–‹‡–Ǧ•’‡ ‹ˆ‹ Ž‹˜‡”’Š‡‘–›’‡Ǥ

(83) ˆ•— ‡••ˆ—ŽǡŠ‘™‡˜‡”ǡ‘–‘Ž›ƒ„‹‘ Š‡‹ ƒŽ Šƒ”ƒ –‡”‹œƒ–‹‘‘ˆ–Š‡ ‘””‡•’‘†‹‰ ‡ŽŽ• ƒ „‡’‡”ˆ‘”‡†ǡ„—–ƒŽ•‘–Š‡› ƒƒŽ•‘„‡—•‡†–‘–‡•––Š‡‡ˆˆ‡ –‘ˆ’‘–‡–‹ƒŽ–”‡ƒ–‡–•–”ƒ–‡‰‹‡• ‘Ž‹˜‡”‡–ƒ„‘Ž‹•Ǥšƒ’Ž‡•‘ˆ’‘–‡–‹ƒŽ–”‡ƒ–‡–•‹ Ž—†‡–Š‡—•‡‘ˆ–Š‡’Š‡›Ž„—–›”ƒ–‡ǡ ƒ Ǧ•’‡ ‹ˆ‹  š‡‘„‹‘–‹  •—„•–ƒ ‡ ƒ† †”—‰ ȋƒ˜‹ –‹Ȍǡ –‘ •–ƒ„‹Ž‹œ‡ –Š‡ ͻͺͷε  —–ƒ–‡†’”‘–‡‹ȏͶͲȂͶʹȐǡ–ƒ”‰‡–‹‰ ‡ƒ–Š‘ ”‘–‡‹ͳͲȋ •’ͳͲȌ–‘‹ ”‡ƒ•‡’”‘–‡‹ ˆ‘Ž†‹‰ ‡ˆˆ‹ ‹‡ › ȏͶ͵Ȑǡ ƒ† •—’’Ž‡‡–ƒ–‹‘ ‘ˆ Ǧ ƒ”‹–‹‡ ȏͶͶȂͶ͹Ȑ ƒ† ‘  ’”‡ —”•‘”• ȏͶͺȂͷʹȐǤ‡ Š‹“—‡•–Šƒ– ƒ„‡—•‡†‘–Š‡‘„–ƒ‹‡†’ƒ–‹‡–ƒ–‡”‹ƒŽ•–‘„‡––‡”—†‡”•–ƒ† –Š‡ Šƒ”ƒ –‡”‹•–‹ •‘ˆ•›’–‘ƒ–‹ ƒ†ƒ•›’–‘ƒ–‹ ‹†‹˜‹†—ƒŽ•ƒ† Šƒ”ƒ –‡”‹•–‹ • ‘ˆ •’‡ ‹ˆ‹   ‹†‹˜‹†—ƒŽ• ‹ Ž—†‡ ™Š‘Ž‡Ǧ‡š‘‡ •‡“—‡ ‹‰ ȋ–‘ ”‡˜‡ƒŽ ‰‡‡–‹  „ƒ ‰”‘—† ƒ† ’‘–‡–‹ƒŽ ‰‡‡–‹  ‘†‹ˆ‹‡”•Ȍǡ  •‡“—‡ ‹‰ ȋ–‘ ”‡˜‡ƒŽ ‰‡‡Ǧ”‡‰—Žƒ–‹‘Ǧ ”‡Žƒ–‡† ƒ†ƒ’–ƒ–‹‘•Ȍǡ –ƒ”‰‡–‡† ƒ† •Š‘–‰— ’”‘–‡‘‹ • ȋ–‘ ”‡˜‡ƒŽ •‘‡ ‘ˆ –Š‡ ˆ— –‹‘ƒŽ ƒ†ƒ’–ƒ–‹‘•Ȍǡ —–ƒ”‰‡–‡† ‡–ƒ„‘Ž‘‹ • ƒ† ˆŽ—š‘‹ • ȋ–Š‡ ”‡˜‡ƒŽ –Š‡ ‘˜‡”ƒŽŽ ‡Ž—Žƒ” ‡–ƒ„‘Ž‹ ’Š‡‘–›’‡ȌǤŠ‡•‡–‡ Š‹“—‡•‹ ‘„‹ƒ–‹‘™‹–Š†‹•‡ƒ•‡Ǧ”‡Ž‡˜ƒ–‡š’‡”‹‡–ƒŽ ‘†‹–‹‘•‹˜‹–”‘‘”‡š˜‹˜‘‹‰Š–”‡˜‡ƒŽ•›’–‘–‘Ž‘‰›Ǧ”‡Žƒ–‡†‰‡‡–‹ ƒ†‡˜‹”‘‡–ƒŽ ‘†‹ˆ‹‡”•ǤŠ‡•ƒŽŽ—„‡”•‘ˆ’ƒ–‹‡–•‹ ‘„‹ƒ–‹‘™‹–Š–Š‡Žƒ”‰‡—„‡”‘ˆ‰‡‡–‹  †‹ˆˆ‡”‡ ‡• –Šƒ– ƒ”‡ —•—ƒŽŽ› ˆ‘—†ǡ ™‹ŽŽ ‡ ‡••‹–ƒ–‡ –‘ ‘„‹‡ –Š‡•‡ Žƒ••‹ ƒŽ Ǯ‘‹ • –‡ Š‘Ž‘‰‹‡•™‹–Š‡ Šƒ‹•–‹ ‘†‡Ž‹‰Ǥ ‡š––‘—•‹‰’ƒ–‹‡–Ǧ†‡”‹˜‡†ƒ–‡”‹ƒŽ•ǡŠ—ƒŠ‡’ƒ–‹  ‡ŽŽŽ‹‡• ‘—Ž†„‡—•‡†–‘—†‡”•–ƒ† ‰‡‡”ƒŽ‡ Šƒ‹••–Šƒ–ƒˆˆ‡ – ™Š‡‹•†‡ˆ‹ ‹‡–Ǥ‘–Š‹•‡†ǡ™‡Šƒ˜‡‰‡‡”ƒ–‡† ƒǦ˜‡”•‹‘‘ˆ–Š‡Š—ƒŠ‡’ƒ–‘ ƒ”‹‘ƒ ‡ŽŽŽ‹‡ ‡’ ʹǡ „›

(84) Ȁƒ•ͻ‰‡‡ ‡†‹–‹‰ –‡ Š‹“—‡ ƒ ‘”†‹‰ –‘ ȏͷ͵Ȑ ȋƒ”–‹‡•ǡ ‹‡‹”ƒ ƒ”ƒǡ —‹Œƒǡ ƒ †‡ Ž—‹• —’—„Ž‹•Š‡†ȌǤŠ‡ ‡’ ʹ ‡ŽŽŽ‹‡™ƒ• Š‘•‡‘—–‘ˆˆ‘—”Š‡’ƒ–‘ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡•ǡ•‹ ‡‹– Šƒ† –Š‡ Š‹‰Š‡•– ‘–‡– ‘ˆ ’”‘–‡‹• ‹˜‘Ž˜‡† ‹ –Š‡   ƒ• †‡–‡”‹‡† „› –ƒ”‰‡–‡† ’”‘–‡‘‹ •ȋ ‹‰—”‡͵ȌǤ  . ʹ͵͵. 7.

(85) Šƒ’–‡”ͽ . A. HepG2. IHH. HUH-7. Hep3B CPT1 liver isoform CPT1 muscle isoform CPT2 VLCAD LCAD MCAD SCAD MTPa MTPb CROT MSCHAD MCKAT. . Relative cell number after 72h (% untreated control). B 150. 100. 100. 100. 50. 50. 50. Control +HoPan. *. 100. ***. 0. ***. 0. 50. 0. IHH. HepG2. 0. HUH-7. Hep3B. . C. KO. KO. KO. KO. KO. KO. KO. MCAD GAPDH. . Figure 3. Generation of an MCAD-KO hepatocyte cell line. Aǣ ‡˜‡Ž• ‘ˆ   ’”‘–‡‹• ‹ –Š‡ Š‡’ƒ–‘ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡ ‡’ ʹǡ–Š‡‹‘”–ƒŽ‹œ‡†Š—ƒŠ‡’ƒ–‘ ›–‡ȋ

(86) Ȍƒ†–Š‡Š‡’ƒ–‘ ƒ” ‹‘ƒ ‡ŽŽ Ž‹‡•  Ǧ͹ƒ† ‡’͵ȋαͳȌǡ†‡–‡”‹‡†ƒ ‘”†‹‰–‘ȏͷͶȐǤŠ‡Š‡ƒ–ƒ’™ƒ•‰‡‡”ƒ–‡†™‹–Š–Š‡‘Ž‹‡ –‘‘Ž ‡–ƒ„‘ƒƒŽ›•– ȏͷͷȐǤ Bǣ  ‡Žƒ–‹˜‡ ‡ŽŽ —„‡” ƒˆ–‡” ͹ʹŠ –”‡ƒ–‡– ™‹–Š ‘ƒ ˜‹–ƒ‹ ͷǦŽƒ ‹‰ ‡†‹—ǤŠ‡ ‡ŽŽ•™‡”‡ —Ž–—”‡†‹–Š‡š‹‰‡ ‡•›•–‡ȋ‘ Š‡’’Ž‹‡† ‹‡ ‡ǡ‡œ„‡”‰ǡ ‡”ƒ›Ǣ ‘ŽŽƒ„‘”ƒ–‹‘™‹–Š”‘ˆǤǤ‘Ž‰ƒȌƒ† ‡ŽŽ‹†‡š˜ƒŽ—‡•™‡”‡ ƒŽ —Žƒ–‡†ƒ ‘”†‹‰–‘ȏͷ͸ȐǤŠ‡ ‡ŽŽ‹†‡š ˜ƒŽ—‡•™‡”‡ ‘•‹†‡”‡†–‘„‡’”‘’‘”–‹‘ƒŽ–‘–Š‡ ‡ŽŽ—„‡”ƒ†—•‡†–Š‹•–‘‡•–‹ƒ–‡–Š‡’‡” ‡–ƒ‰‡‘ˆ ”‡ƒ‹‹‰ ‡ŽŽ•ƒˆ–‡” ‘ƒ–”‡ƒ–‡–Ǥ ‘ƒ™ƒ•ƒ‹†‰‹ˆ–ˆ”‘”‘ˆǤǤ‹„‘Ǥ‡•—Ž–•ƒ”‡•Š‘™ƒ•‹ „ƒ” ’Ž‘–• ƒ• ‡ƒ ά ǡ α͵Ǧ͸ ’‡” ‰”‘—’ǡ ȗ’δͲǤͲͷǡ ȗȗȗ’δͲǤͲͲͲͳ —•‹‰ —’ƒ‹”‡† –Ǧ–‡•–Ǥ C: ‡•–‡” Ž‘– ƒƒŽ›•‹•’”‘–‡‹Ž‡˜‡Ž•‹ƒ•‡Ž‡ –‹‘‘ˆ ‡’ ʹ Ž‘‡•Ǥ Ž› ‡”ƒŽ†‡Š›†‡͵Ǧ’Š‘•’Šƒ–‡†‡Š›†”‘‰‡ƒ•‡ ȋ  Ȍ™ƒ•—•‡†ƒ•–Š‡Š‘—•‡Š‘Ž†‰‡‡Ǥ‡’‹ –‡†Š‡”‡‹•–Š‡„Ž‘– ‘–ƒ‹‹‰–Š‡ Š‘•‡ ‡’ ʹ ȋŽƒ‡ͷȌǤ . Š‡ ™‹Ž†Ǧ–›’‡ ‡’ ʹ ‡ŽŽ Ž‹‡ ™ƒ• ƒŽ•‘ •‡•‹–‹˜‡ –‘ –Š‡ ‘  •›–Š‡•‹• ‹Š‹„‹–‘” ‘’ƒ–‡ƒ–‡ȋ ‘ƒȌ‹‡†‹—™‹–Š‘—––Š‡‘ ’”‡ —”•‘”‹–ƒ‹ͷȋ ‹‰—”‡͵ȌǤŠ‹• ™‹ŽŽ„‡”‡Ž‡˜ƒ––‘•–—†›–Š‡‹–‡”’Žƒ›„‡–™‡‡‘ ƒ˜ƒ‹Žƒ„‹Ž‹–›ƒ† Ǥ

(87) ’”‘ ‡‡†‡† ™‹–Š–Š‡Ǧ ‡’ ʹ Ž‘‡™‹–Š–Š‡ Ž‡ƒ‡•–•‡“—‡ ‡ȋŽƒ‡ͷ‹ ‹‰—”‡͵ȌǤŠ‡ ‡’ ʹ ‡ŽŽ• ƒ”‡ —Ž–—”‡† ‹ ʹΨ Š—ƒ •‡”—ǡ –Š‡› ”‡•‡„Ž‡• ’”‹ƒ”› Š—ƒ Š‡’ƒ–‘ ›–‡ ‘”‡ –Šƒ ™Š‡ –Š‡› ƒ”‡ —Ž–—”‡† ‹  ͳͲΨ ˆ‡–ƒŽ ƒŽˆ •‡”— ȏͷ͹ȂͷͻȐǤ

(88) †‡‡†ǡ —’‘ ˜‹•—ƒŽ ‹•’‡ –‹‘

(89)  ‘•‹•–‡–Ž›‘–‹ ‡†–Šƒ––Š‡‘”’Š‘Ž‘‰›‘ˆ„‘–Š–Š‡ƒ†Ǧ ‡’ ʹ. ʹ͵Ͷ.

(90) ‡‡”ƒŽ†‹• —••‹‘ ‡ŽŽ• •–ƒ”–‡† ”‡•‡„Ž‹‰ –Šƒ– ‘ˆ ’”‹ƒ”› Š‡’ƒ–‘ ›–‡• ‹ –Š‡ ʹΨ Š—ƒ •‡”—Ǥ ‘”‡‘˜‡”ǡ Ǧ —Ž–—”‡••Š‘™‡†Ž‡••†‹˜‹†‹‰ ‡ŽŽ• ‘’ƒ”‡†–‘–Š‡ ‡ŽŽ•ȋ†ƒ–ƒ‘–•Š‘™ȌǤŠ‡ ‡š– •–‡’ ™‹ŽŽ  „‡ –‘ ƒƒŽ›•‡ „‹‘ Š‡‹ ƒŽŽ› –‘ ™Šƒ– ‡š–‡– –Š‡•‡ ‡ŽŽ• ‡šŠ‹„‹– ƒ Ž‹˜‡”ǦŽ‹‡ ‡–ƒ„‘Ž‹  ’Š‡‘–›’‡ ȋ ˆǤȏ͸ͲȐȌǤ Š‡ –Š‡ Ǧ ‡’ ʹ ‡ŽŽ Ž‹‡ ™‹ŽŽ ’”‘˜‹†‡ ƒ ˜‡”› ’”ƒ –‹ ƒŽ‹˜‹–”‘•›•–‡–‘‹˜‡•–‹‰ƒ–‡–Š‡‹–‡”’Žƒ›‘ˆ–Š‡ ’ƒ–Š™ƒ›™‹–Š•—””‘—†‹‰ ’ƒ–Š™ƒ›• ƒ† –‘ ˜ƒŽ‹†ƒ–‡ ‘’—–‡” •‹—Žƒ–‹‘•Ǥ šƒ’Ž‡• ‹ Ž—†‡ –Š‡ ‡ˆˆ‡ – ‘ˆ ‘  †‡’Ž‡–‹‘ƒ†Ž‘™Ǧ ƒ”‹–‹‡‘ ˆŽ—šǡ‰Ž— ‘•‡’”‘†— –‹‘ǡ‡–‘‡„‘†›’”‘†— –‹‘ƒ† ‡ŽŽ˜‹ƒ„‹Ž‹–›‹–Š‡Ǧ ‘’ƒ”‡†–‘–Š‡ ‡’ ʹ ‡ŽŽ•Ǥ . Conclusion Š‹• –Š‡•‹• ”‡’”‡•‡–• ƒ ˆ‹”•– ‡š’Ž‘”ƒ–‹‘ ‹–‘  †‡ˆ‹ ‹‡ › —•‹‰ ƒ ‘„‹ƒ–‹‘ ‘ˆ ›•–‡• ‡†‹ ‹‡ –‘‘Ž•Ǥ Š‡ ™‘” ’”‘˜‹†‡† ‹•‹‰Š– ‹–‘ –Š‡ Ž‹‹–ƒ–‹‘•ǡ ƒ†˜ƒ–ƒ‰‡• ƒ† †‹•ƒ†˜ƒ–ƒ‰‡• ‘ˆ ‘’—–ƒ–‹‘ƒŽ ‘†‡Ž‹‰ǡ ‹ ˜‹˜‘ ‡š’‡”‹‡–• ‹ ‹ ‡ ƒ† ‹ ˜‹–”‘ ‡š’‡”‹‡–•‹Š—ƒƒ–‡”‹ƒŽǤ‡‘ˆ›‡›‘˜‡”ƒ” Š‹‰ˆ‹†‹‰•ǡ„‘–Š‹•‹Ž‹ ‘ƒ†‹˜‹˜‘ǡ ‹•–Š‡”‘Ž‡‘ˆ‘‡œ›‡ƒ†ȋȌȋ Ȍ‹ ˆ— –‹‘ƒ††‡ˆ‹ ‹‡ ›ǤŠ‡Š—ƒ ˜‡”•‹‘‘ˆ–Š‡ ‘’—–ƒ–‹‘ƒŽ‘†‡ŽȋChapter 5Ȍ‘ˆˆ‡”•–Š‡‘’’‘”–—‹–›–‘‹–‡‰”ƒ–‡Š—ƒ †ƒ–ƒǡ‡Ǥ‰Ǥˆ”‘‹˜‹–”‘‡š’‡”‹‡–•™‹–Š’ƒ–‹‡–Ǧ•’‡ ‹ˆ‹  ‡ŽŽ•‘”–Š‡‡™Ǧ ‡’ ʹ ‡ŽŽŽ‹‡ǤŠ—•ǡ

(91) Š‘’‡–Šƒ––Š‡ ‘’”‡Š‡•‹˜‡‰”‘—†™‘”ƒ††‹• —••‹‘•Žƒ‹†‘—–‹ –Š‹• –Š‡•‹• •Š‘™ ’”‘‹•‡ ˆ‘” ˆ—–—”‡ ˆ‘ŽŽ‘™Ǧ—’ •–—†‹‡• –‘ —†‡”•–ƒ† –Š‡ ‡ Šƒ‹•• —†‡”Ž›‹‰ –Š‡ Š‡–‡”‘‰‡‡‘—• ’Š‡‘–›’‡• ‹  †‡ˆ‹ ‹‡ ›Ǥ Š‹• •Š‘—Ž† ‘’‡ —’ ‡™ ƒ˜‡—‡• ˆ‘” ‘”‡ ’‡”•‘ƒŽ‹œ‡† †‹ƒ‰‘•‡•ǡ ’”‘‰‘•‡• ƒ† –”‡ƒ–‡– •–”ƒ–‡‰‹‡• ˆ‘”  †‡ˆ‹ ‹‡ ›Ǥ . References ͳǤ ʹǤ ͵Ǥ ͶǤ ͷǤ ͸Ǥ ͹Ǥ ͺǤ ͻǤ. ͳͲǤ ͳͳǤ. ƒ”–‹‡•Ǧ ǡ˜ƒ—‡ǡ‡‹Œ‰‘—†Ǧ ǡƒ‡”ǤŠ‡’”‘‹• —‘—•‡œ›‡‡†‹—Ǧ Šƒ‹ ͵Ǧ‡–‘Ǧƒ ›ŽǦ‘ –Š‹‘Žƒ•‡ –”‹‰‰‡”• ƒ ˜‹ ‹‘—• › Ž‡ ‹ ˆƒ––›Ǧƒ ‹† „‡–ƒǦ‘š‹†ƒ–‹‘Ǥ  ‘’—–‹‘ŽǤʹͲͳ͹Ǣͳ͵ȋͶȌǣͳȂʹʹǤ ƒ—”‘ Ǥ‘””‡ –‹‘–‘Dz‘–”‘Žƒ†”‡‰—Žƒ–‹‘‘ˆ’ƒ–Š™ƒ›•˜‹ƒ‡‰ƒ–‹˜‡ˆ‡‡†„ƒ dzǤ ‘ 

(92) –‡”ˆƒ ‡ǤʹͲͳ͹ǢͳͶȋͳʹͻȌǤ  Ǥ Š‡ ‹‡–‹ • ‘ˆ ‡œ›‡Ǧ ƒ–ƒŽ›œ‡† ”‡ƒ –‹‘• ™‹–Š –™‘ ‘” ‘”‡ •—„•–”ƒ–‡• ‘” ’”‘†— –•Ǥ

(93) Ǥ‘‡ Žƒ–—”‡ƒ†”ƒ–‡‡“—ƒ–‹‘•Ǥ‹‘ Š‹‹‘’Š›• –ƒǤͳͻ͸͵ ƒͺǢ͸͹ȋʹȌǣͳͲͶȂ͵͹Ǥ ‹‡„‡”‡‹•–‡” ǡ Ž‹’’ Ǥ ”‹‰‹‰ ‡–ƒ„‘Ž‹  ‡–™‘”• –‘ Ž‹ˆ‡ǣ ‘˜‡‹‡ ‡ ”ƒ–‡ Žƒ™ ƒ† –Š‡”‘†›ƒ‹  ‘•–”ƒ‹–•ǤŠ‡‘”‹‘Ž‡†‘†‡ŽǤʹͲͲ͸Ǣ͵Ǥ  ‡ƒǡ ”‡”ƒ ǡ‹‡Ž‡Ǥ ‡‡”ƒŽƒ ›ŽǦ‘†‡Š›†”‘‰‡ƒ•‡ˆ”‘’‹‰Ž‹˜‡”Ǥ‹‡–‹  ƒ†„‹†‹‰•–—†‹‡•Ǥ ‹‘ŽŠ‡Ǥͳͻ͹ͻ’”ʹͷǢʹͷͶȋͺȌǣʹ͹͵ͲȂͷǤ ŽƒŠ‘Žœ ǡ ‘‘” ǡ ƒ”Ǧ˜‡ ǡ ‹Ž‘ Ǥ —‹Ž‹„”ƒ–‘” Ǧ Š‡ „‹‘ Š‡‹ ƒŽ –Š‡”‘†›ƒ‹ • ƒŽ —Žƒ–‘”Ǥ— Ž‡‹  ‹†•‡•ǤʹͲͳʹǢͶͲȋͳȌǣ͹͹ͲȂͷǤ —‰‹ Ǥ ›ƒ‹  ‹‡–‹  ‘†‡Ž‹‰ ‘ˆ ‹–‘ Š‘†”‹ƒŽ ‡”‰› ‡–ƒ„‘Ž‹•Ǥ Ǧ‡ŽŽ ›•– ƒ•‹  ‘ ‡’–•’’ŽǤʹͲͳ͵ǢͳͲͷȂͶʹǤ ˜ƒ—‡ǡ‹‘• ǡ ‡”†‹‰ǡŽ‡‡‡”ǡ†‡‡•–‡ ǡ‘—™ǡ ‘—–‡ǡ ”‘‡ ǡ”ƒ„ǡ‡‹Œ‰‘—† ǡƒ‡”Ǥ‹‘ Š‡‹ ƒŽ‘’‡–‹–‹‘ƒ‡• ƒ––›Ǧ ‹†ȾǦš‹†ƒ–‹‘ —Ž‡”ƒ„Ž‡–‘—„•–”ƒ–‡˜‡”Ž‘ƒ†Ǥ‘‘’—–‹‘ŽǤʹͲͳ͵ǢͻȋͺȌǣʹȂͻǤ ˜ƒ—‡ǡ‘Ž‡”Ǧ‘—™ǡ ‡”†‹‰ǡŽ‡‡‡”ǡ‘Ž–‡”• ǡ˜ƒ‹Œ– ǡƒ”–‹‡• ǡ ‹‡œ‡Ǧ‘‹‰ǡ ‡‹‡”ǡ‡”‡–‹‡” ǡ ”‘‡ǡ‡‹Œ‰‘—† ǡ‡”• ǡƒ‡”Ǥ ‹˜‹‰‘–Š‡‡†‰‡ǣ—„•–”ƒ–‡ ‘’‡–‹–‹‘‡š’Žƒ‹•Ž‘••‘ˆ”‘„—•–‡••‹‹–‘ Š‘†”‹ƒŽˆƒ––›Ǧ ƒ ‹†‘š‹†ƒ–‹‘†‹•‘”†‡”•Ǥ‹‘ŽǤʹͲͳ͸ǢͳͶȋͳȌǣͳȂͳͷǤ ˜ƒ—‡ǡ‹‘• ǡ ‡”†‹‰ǡŽ‡‡‡”ǡ†‡‡•–‡ ǡ‘—™ǡ ‘—–‡ǡ ”‘‡ ǡ”ƒ„ǡ‡‹Œ‰‘—† ǡƒ‡”Ǥ‹‘ Š‡‹ ƒŽ‘’‡–‹–‹‘ƒ‡• ƒ––›Ǧ ‹†ȾǦš‹†ƒ–‹‘ —Ž‡”ƒ„Ž‡–‘—„•–”ƒ–‡˜‡”Ž‘ƒ†Ǥ‘‘’—–‹‘ŽǤʹͲͳ͵ǢͻȋͺȌǣʹȂͻǤ –ƒŽ‡›ǡ ƒŽ‡ǡ‘ƒ–‡•ǡ ƒŽŽǡ‘”‡›ǡƒ‰ǡ‡ŽŽ‡›

(94) ǡ ‘œƒŽ‡•ǡ‹ŽŽ‹ƒ•‘. ʹ͵ͷ. 7.

(95) Šƒ’–‡”ͽ. ͳʹǤ ͳ͵Ǥ ͳͶǤ ͳͷǤ ͳ͸Ǥ ͳ͹Ǥ. ͳͺǤ ͳͻǤ ʹͲǤ ʹͳǤ ʹʹǤ ʹ͵Ǥ ʹͶǤ ʹͷǤ ʹ͸Ǥ ʹ͹Ǥ ʹͺǤ ʹͻǤ. ͵ͲǤ. ͵ͳǤ. ʹ͵͸. ǡ ƒ‡” Ǥ ‡†‹—Ǧ Šƒ‹ ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡ †‡ˆ‹ ‹‡ › ‹ Š‹Ž†”‡ ™‹–Š ‘Ǧ‡–‘–‹  Š›’‘‰Ž› ‡‹ƒƒ†Ž‘™ ƒ”‹–‹‡Ž‡˜‡Ž•Ǥ‡†‹ƒ–”‡•Ǥͳͻͺ͵Ǣͳ͹ȋͳͳȌǣͺ͹͹ȂͺͶǤ Žƒ ǡƒ˜‹† ǡ„”ƒ‹ǡ‹‰Ž‹‘œœ‹ǡ”ƒ† ǡò”‰‹ ǡ˜ƒ†‡” ‘‘– Ǥ™‹••ƒŽǣ”‘–‡‹ ƒŽ‹–‘›Žƒ–‹‘†ƒ–ƒ„ƒ•‡Ǥ ͳͲͲͲ‡•‡ƒ” ŠǤʹͲͳͷǢͶȋͲȌǣʹ͸ͳǤ — ǡŠ‘— ǡ‹ǡ‡‰ǡŠƒ‰ǡ—‡Ǥǣ—’†ƒ–‡††ƒ–ƒ”‡•‘—” ‡‘ˆ’”‘–‡‹Ž›•‹‡ ‘†‹ˆ‹ ƒ–‹‘•Ǥ  ‡‡– ‡‘‹ •ǤʹͲͳ͹ƒ›ʹͲǢͶͶȋͷȌǣʹͶ͵ȂͷͲǤ ‘—‰‘˜‹ƒǡ–‡”‹‡ ǡƒ†‡”• ǡ ‘—–‡ǡ†‡‘‡” Ǥ„‡””ƒ–’”‘–‡‹ƒ ›Žƒ–‹‘‹• ƒ ‘‘ ‘„•‡”˜ƒ–‹‘ ‹ ‹„‘” ‡””‘”• ‘ˆ ƒ ›ŽǦ‘ ‡–ƒ„‘Ž‹•Ǥ 

(96) Š‡”‹– ‡–ƒ„ ‹•Ǥ ʹͲͳͶǢ͵͹ȋͷȌǣ͹ͲͻȂͳͶǤ —†ƒ‰‘––‘ǡƒŽ‡”ƒ”‘Ǥ”‘–‡‹’‘•–Ǧ–”ƒ•Žƒ–‹‘ƒŽ‘†‹ˆ‹ ƒ–‹‘•ǣ

(97) •‹Ž‹ ‘’”‡†‹ –‹‘–‘‘Ž• ƒ†‘Ž‡ —Žƒ”‘†‡Ž‹‰Ǥ‘’—––”— –‹‘–‡ Š‘Ž ǤʹͲͳ͹Ǣͳͷǣ͵Ͳ͹ȂͳͻǤ — ǡ ƒ‰ ǡ ‹ ǡ ‡‰ ǡ ‡‰ ǡ —‹ ǡ —‡ Ǥ ǣ  ƒ–ƒ„ƒ•‡ ‘ˆ —ƒ ‹•‡ƒ•‡Ǧ ƒ••‘ ‹ƒ–‡† ‘•–Ǧ–”ƒ•Žƒ–‹‘ƒŽ ‘†‹ˆ‹ ƒ–‹‘•Ǥ ‡‘‹ • ”‘–‡‘‹ • ‹‘‹ˆ‘”ƒ–‹ •Ǥ ʹͲͳͺǢͳ͸ȋͶȌǣʹͶͶȂͷͳǤ ƒ’—‡–‡Ǧ”— ǡ ‘”‡‘Ǧ‘•Š—‡”–‘• ǡ  ‹Ǧ‡”‡œ ǡ ƒ–‘””‡Ǧ‡ŽŽ‹ ‡” ǡ ‘Žƒ• ǡ ƒŽ•ƒ ǡ ‡”ƒŽ‡•ǦŽ‡‡–‡ǡ—‹”‘•ǡƒŽ˜‘ǡ‘†”‹‰—‡œǦ ‡”ƒ†‡œǡƒ˜ƒ•ǡ”—œǡƒ””ƒ ‡†‘ ǡ ‘’‡œǦ–‹ ǡ ‡”‡œǦƒ”–‘• ǡ ‡”ƒ†‡œǦ‹Ž˜ƒ ǡ ‡”ƒ†‡œǦ‹œƒ””ƒ ǡ ”‹“—‡œ Ǥ —’‡” ‘’Ž‡š ••‡„Ž› ‡–‡”‹‡• Ž‡ –”‘ Ž—š ‹ –Š‡ ‹–‘ Š‘†”‹ƒŽ Ž‡ –”‘ ”ƒ•’‘”– Šƒ‹Ǥ ‹‡ ‡ȋͺͲǦȌǤʹͲͳ͵Ǣ͵ͶͲȋ͸ͳͶͲȌǣͳͷ͸͹Ȃ͹ͲǤ Šƒǡƒ‰ǡ—™‡”š ǤƒŽ›•‹•‘ˆ‹–‘ Š‘†”‹ƒŽ‡•’‹”ƒ–‘”›Šƒ‹—’‡” ‘’Ž‡š‡••‹‰ Ž—‡ ƒ–‹˜‡ ‘Ž›ƒ ”›Žƒ‹†‡ ‡Ž Ž‡ –”‘’Š‘”‡•‹• ȋǦ ȌǤ —”” ”‘–‘  ‘—•‡ ‹‘ŽǤ ʹͲͳ͸Ǣ͸ȋͳȌǣͳȂͳͶǤ ‘‰Ž‹ƒ–‹ ǡ ƒŽ˜‘ ǡ ‘—”‡‹”‘ ǡ —ƒ”ƒ• ǡ ‹‡–‘Ǧ”‡ŽŽƒ‘ ǡ ƒ” ‹ƒǦ‘›ƒ–‘• ǡ œ—”†‹ƒ

(98) ǡ ‡” ƒ†‡”ǡžœ“—‡œ ǡ”‹“—‡œ Ǥ‡ Šƒ‹•‘ˆ•—’‡”Ǧƒ••‡„Ž›‘ˆ”‡•’‹”ƒ–‘”› ‘’Ž‡š‡•

(99)

(100)

(101)  ƒ†

(102) Ǥƒ–—”‡ǤʹͲͳ͸Ǣͷ͵ͻȋ͹͸͵ͲȌǣͷ͹ͻȂͺʹǤ ‘—”‹‡” ǡ ƒ–‹  ǡ —œœ‡‡–‡ ǡ ƒ”••‘ Ǧ ǡ ‹Ž‡‘˜‹  Ǥ Š‡ ”‡•’‹”ƒ–‘”› Šƒ‹ •—’‡” ‘’Ž‡š ‘”‰ƒ‹œƒ–‹‘ ‹• ‹†‡’‡†‡– ‘ˆ ͹ƒʹŽ ‹•‘ˆ‘”•Ǥ ‡ŽŽ ‡–ƒ„Ǥ ʹͲͳͶ ‡  ʹǢʹͲȋ͸ȌǣͳͲ͸ͻȂ͹ͷǤ ‹ŽŽ‹ƒ• ǡ—ǡ Šƒǡ—„—‹•ǡŽƒ––ƒǡ”‰ƒǡ ‘—–‡ǡƒ”‹—–ƒǡ‘Ž•‹ ǡ ƒ„‘‹ ǡ ‡„‡”•‘Ž† ǡ —™‡”š Ǥ ›•–‡• ’”‘–‡‘‹ • ‘ˆ Ž‹˜‡” ‹–‘ Š‘†”‹ƒ ˆ— –‹‘Ǥ  ‹‡ ‡ǤʹͲͳ͸ —ͳͲǢ͵ͷʹȋ͸ʹͻͳȌǣƒƒ†ͲͳͺͻǤ Š‹„ƒ ǡ

(103) ‡†ƒ ǡ ‘”‹‡Ǧ

(104) ‘—‡ ǡ ƒƒ›ƒƒ ǡ ƒƒƒ ǡ

(105) ‘—‡ Ǥ ‡ˆ‹ ‹‡ › ‘ˆ ͹ǡ ƒ ‹–‘ Š‘†”‹ƒŽ•—’‡” ‘’Ž‡šƒ••‡„Ž›’”‘‘–‹‰ˆƒ –‘”ǡŽ‘™‡”•„Ž‘‘†‰Ž— ‘•‡Ž‡˜‡Ž‹‹ ‡Ǥ ‹ ‡’ǤʹͲͳ͹Ǣ͹ȋͳȌǣ͹͸Ͳ͸Ǥ ‹Ž‡‘˜‹ ǡŽƒœƒ ǡƒ”••‘ ǡ ‹”•– ǤŠ‡‹‰ƒ‘ˆ–Š‡‡•’‹”ƒ–‘”›Šƒ‹—’‡” ‘’Ž‡šǤ ‡ŽŽ‡–ƒ„ǤʹͲͳ͹ǢʹͷȋͶȌǣ͹͸ͷȂ͹͸Ǥ ƒ–ƒ—–‹ǡŽ‹‰ƒǡ‡‹‰• ǡ ”‘‘–Š—‹• Ǥ ƒŽ‹†ƒ–‹‘‘ˆ’”‡ ‹•‹‘Ǧ —–Ž‹˜‡”•Ž‹ ‡•–‘ •–—†›†”—‰Ǧ‹†— ‡† Š‘Ž‡•–ƒ•‹•ǣƒ–”ƒ• ”‹’–‘‹ •ƒ’’”‘ƒ ŠǤ” Š‘š‹ ‘ŽǤʹͲͳ͹Ǣͻͳȋ͵ȌǣͳͶͲͳȂ ͳʹǤ ‘Šǡ ƒ”ˆ‹‡ŽǤ‘’—–‡”•‹—Žƒ–‹‘‘ˆ‡–ƒ„‘Ž‹•‹’ƒŽ‹–ƒ–‡Ǧ’‡”ˆ—•‡†”ƒ–Š‡ƒ”–Ǥ

(106) Ǥ ƒŽ‹–ƒ–‡‘š‹†ƒ–‹‘Ǥ‹‘‡†‰Ǥͳͻͺ͵ǢͳͳȋͷȌǣ͵͸ͳȂͺͶǤ —‰‹ ǡ ‘‹–ƒ Ǥ  ‰‡‡”ƒŽ ‘’—–ƒ–‹‘ƒŽ ‘†‡Ž ‘ˆ ‹–‘ Š‘†”‹ƒŽ ‡–ƒ„‘Ž‹• ‹ ƒ ™Š‘Ž‡ ‘”‰ƒ‡ŽŽ‡• ƒŽ‡Ǥ‹‘‹ˆ‘”ƒ–‹ •ǤʹͲͲͶǢʹͲȋͳͳȌǣͳ͹ͻͷȂ͸Ǥ ‹– Š‡ŽŽ ǡ ƒ—–Š‹‡”ǡ‡•‹’Ž‡ǡƒ‰ǡƒ‡”ǡ—”‡•Š‹

(107) Ǥ ‡”‡†‹–ƒ”›ƒ†ƒ “—‹”‡† †‹•‡ƒ•‡•‘ˆƒ ›ŽǦ ‘‡œ›‡‡–ƒ„‘Ž‹•Ǥ‘Ž ‡‡–‡–ƒ„ǤʹͲͲͺǢͻͶȋͳȌǣͶȂͳͷǤ ƒ‰ ǡŠƒ‘ǡƒ‰ǡƒ‰ǡ‹– Š‡ŽŽ Ǥ ‡”‡†‹–ƒ”›†‹•‡ƒ•‡•‘ˆ ‘‡œ›‡–Š‹‘‡•–‡” ‡–ƒ„‘Ž‹•Ǥ‹‘ Š‡‘ ”ƒ•ǤʹͲͳͻ ‡„ʹͺǢͶ͹ȋͳȌǣͳͶͻȂͷͷǤ ‹ǡƒŒ‹ƒǡŠ‹—”ƒǡƒ”‡›ǡ–”‘—†ǡ—”ƒ›ƒƒǡŠ–ƒ‡ǡ ‡œ‹‡Ǥ‘••‘ˆ –Š‡ ‹–‘ Š‘†”‹ƒŽ ƒ––›  ‹† ȾǦš‹†ƒ–‹‘ ”‘–‡‹ ‡†‹—ǦŠƒ‹  ›ŽǦ‘‡œ›‡  ‡Š›†”‘‰‡ƒ•‡ ‹•”—’–•š‹†ƒ–‹˜‡ Š‘•’Š‘”›Žƒ–‹‘”‘–‡‹‘’Ž‡š –ƒ„‹Ž‹–›ƒ† — –‹‘Ǥ  ‹‡’ǤʹͲͳͺǢͺȋͳȌǣͳȂͳ͹Ǥ ‡”• ǡ‘—™ǡ‹„ƒ• ǡ‹ƒ ‹‹ ǡƒœ‹ǡ‡‰”‡––‘ ǡ‡• ƒǡ‡‹Œ‰‘—† ǡ ‹– ǡ ƒŒ‡” ǡ ƒ”‰ƒ• Ǥ š’‡”‹‡–ƒŽ ‡˜‹†‡ ‡ ˆ‘” ’”‘–‡‹ ‘š‹†ƒ–‹˜‡ †ƒƒ‰‡ ƒ† ƒŽ–‡”‡†ƒ–‹‘š‹†ƒ–†‡ˆ‡•‡‹’ƒ–‹‡–•™‹–Š‡†‹—Ǧ Šƒ‹ƒ ›ŽǦ‘†‡Š›†”‘‰‡ƒ•‡†‡ˆ‹ ‹‡ ›Ǥ 

(108) Š‡”‹–‡–ƒ„‹•ǤʹͲͳͶǢ͵͹ȋͷȌǣ͹ͺ͵ȂͻǤ ‹ ‘š ǡ ‡‘‰Š‡‰ƒ ǡ ƒ• Š‡ ǡ ‡•ƒ”† ǡ ƒ•“—ƒŽ‹ ǡ ‹ƒ‘ ǡ ‡‡ ǡ ‹ƒ‰ ǡ — 

(109) ǡ.

(110) ‡‡”ƒŽ†‹• —••‹‘. ͵ʹǤ ͵͵Ǥ ͵ͶǤ ͵ͷǤ ͵͸Ǥ ͵͹Ǥ ͵ͺǤ ͵ͻǤ ͶͲǤ ͶͳǤ ͶʹǤ Ͷ͵Ǥ. ͶͶǤ ͶͷǤ Ͷ͸Ǥ Ͷ͹Ǥ ͶͺǤ ͶͻǤ ͷͲǤ. ͷͳǤ ͷʹǤ ͷ͵Ǥ. ‡”•Šƒ™ǡ‘ƒ–‘ ǡ’–‡ǡ‘‰‘ǡ—––‡” ǡ Š”‡‹„‡”ǡ‡ Š‡”ǡ‘š ǡ‹ŽŽƒ—‡˜ƒ Ǥ. Ž‘„ƒŽƒŽ›•‹•‘ˆŽƒ•ƒ‹’‹†•

(111) †‡–‹ˆ‹‡•‹˜‡”Ǧ‡”‹˜‡† ›Ž ƒ”‹–‹‡•ƒ•ƒ —‡Ž‘—” ‡ˆ‘” ”‘™ ƒ–Š‡”‘‰‡‡•‹•Ǥ‡ŽŽ‡–ƒ„ǤʹͲͳ͹Ǣʹ͸ȋ͵ȌǣͷͲͻȂͷʹʹǤ‡͸Ǥ „—”ƒ†ǤŠ‡‹˜‡”ƒ•ƒ —„‹Š‡”‘‰‡‡•‹•Ǥ‡ŽŽ‡–ƒ„ǤʹͲͳ͹Ǣʹ͸ȋ͵ȌǣͶͷͶȂͷǤ —‹ ǡ Š‡”‰—”‘˜‹ Š ǡ ‘”• Š‡”  ǡ ƒ‰ ǡ ‡‰ ǡ — ǡ •’ƒ”œƒ ǡ ‡›ƒ ǡ ‡ Šƒǡ ƒš‹ƒ‰ —‘ ǡ Š‹–‡ ǡ ƒ„‹‘™‹–œ Ǥ Ž— ‘•‡ ˆ‡‡†• –Š‡  › Ž‡ ˜‹ƒ ‹” —Žƒ–‹‰ Žƒ –ƒ–‡Ǥ ƒ–—”‡ǤʹͲͳ͹Ǣͷͷͳȋ͹͸͹ͺȌǣͳͳͷȂͺǤ —ƒ”ǡŽƒ‰‡”‘ ǡ—””ƒ Ǥ

(112) †— ‡†’Ž—”‹’‘–‡–•–‡ ‡ŽŽ•‹†‹•‡ƒ•‡‘†‡Ž‹‰ƒ†‰‡‡ ‹†‡–‹ˆ‹ ƒ–‹‘Ǥ‡–Š‘†•‘Ž‹‘ŽǤʹͲͳͺǢͳ͹Ͳ͸ǣͳ͹Ȃ͵ͺǤ —––ƒǡ ‡‘

(113) ǡŽ‡˜‡”• Ǥ‹•‡ƒ•‡‘†‡Ž‹‰‹–‡‡ŽŽǦ‡”‹˜‡†͵”‰ƒ‘‹†›•–‡•Ǥ”‡†• ‘Ž‡†ǤʹͲͳ͹Ǣʹ͵ȋͷȌǣ͵ͻ͵ȂͶͳͲǤ — Šǡ‘„Ž‹ Š ǡ—–‘Žˆǡƒ”–‹‡œǦ”‹ƒ•ǤŠ‡Š‘’‡ƒ†–Š‡Š›’‡‘ˆ‘”‰ƒ‘‹†”‡•‡ƒ” ŠǤ ‡˜‡Ž‘’‡–ǤʹͲͳ͹ǢͳͶͶȋ͸Ȍǣͻ͵ͺȂͶͳǤ ƒ‰ ǡ—ǡ‹—ǡƒ‘Ǥƒ–‹‡–Ǧ†‡”‹˜‡†‘”‰ƒ‘‹†•ǣƒ’”‘‹•‹‰‘†‡Žˆ‘”’‡”•‘ƒŽ‹œ‡† ƒ ‡”–”‡ƒ–‡–Ǥ ƒ•–”‘‡–‡”‘Ž‡’ǤʹͲͳͺǢ͸ȋͶȌǣʹͶ͵ȂͷǤ ƒ††”‹ ǡ‹’•‘Ǥ”‰ƒǦ‘ǦƒǦ Š‹’–‡ Š‘Ž‘‰›ǣ–—”‹‰–‹–•’‘–‡–‹ƒŽˆ‘” Ž‹‹ ƒŽ„‡‡ˆ‹– ‹–‘”‡ƒŽ‹–›Ǥ”—‰‹• ‘˜‘†ƒ›ǤʹͲͳͻǢͲͲȋͲͲȌǤ ‡ ™‹–– ǡŽƒ”ǡŠ‡‡Ž‡”ǡƒ›Ž‘”ǡ–‘Žœǡ ”‹ˆˆ‹–Šǡ‡ŽŽ•Ǥ‹˜‡”Ǯ‘”‰ƒ‘ƒ Š‹’Ǥǯ š’‡ŽŽ‡•ǤʹͲͳͺǢ͵͸͵ȋͳȌǣͳͷȂʹͷǤ ƒ‰ Ǥ š’Ž‘”‹‰ –Š‡”ƒ’‡—–‹  ƒ’’”‘ƒ Š‡• ˆ‘” –”‡ƒ–‡– ‘ˆ ‡†‹—Ǧ Šƒ‹ ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡ȋȌ†‡ˆ‹ ‹‡ ›ǤʹͲͳͶǤ ‘ Ž‡› Ǥ •‡ ‘ˆ ƒ˜‹ –‹ ‹ ƒ–‹‡–• ‹–Š  ‡ˆ‹ ‹‡ › ‹–Š –Š‡ ͻͺͷε  ȋ͵ͲͶȌ —–ƒ–‹‘ ȏ

(114) –‡”‡–ȐǤ ʹͲͳ͹ ȏ ‹–‡† ʹͲͳͻ ’” ʹͳȐǤ ˜ƒ‹Žƒ„Ž‡ ˆ”‘ǣ Š––’•ǣȀȀ Ž‹‹ ƒŽ–”‹ƒŽ•Ǥ‰‘˜Ȁ –ʹȀ•Š‘™Ȁ•–—†›ȀͲͳͺͺͳͻͺͶ ƒŽ‹” ǡ —‹–‡” ǡ ƒ†‡”•  ǡ ‘—–‘‘’‡”  Ǥ

(115) †‡–‹ˆ‹ ƒ–‹‘ ‘ˆ ‡œ›‡• ‹˜‘Ž˜‡† ‹ ‘š‹†ƒ–‹‘‘ˆ’Š‡›Ž„—–›”ƒ–‡Ǥ ‹’‹†‡•ǤʹͲͳ͹ǢͷͺȋͷȌǣͻͷͷȂ͸ͳǤ —ǡŠ‡ǡ’‘–‡ǡƒ––ƒ‰Ž‹ƒǡ — ‡ǡƒ Ǥ”‘Ž‘‰‡†ˆƒ•–‹‰‹†‡–‹ˆ‹‡•Š‡ƒ–•Š‘  ’”‘–‡‹ͳͲƒ•ƒ•‹”–—‹͵•—„•–”ƒ–‡ǣŽ— ‹†ƒ–‹‰ƒ‡™‡ Šƒ‹•Ž‹‹‰‹–‘ Š‘†”‹ƒŽ’”‘–‡‹ ƒ ‡–›Žƒ–‹‘–‘ˆƒ––›ƒ ‹†‘š‹†ƒ–‹‘‡œ›‡ˆ‘Ž†‹‰ƒ†ˆ— –‹‘Ǥ ‹‘ŽŠ‡ǤʹͲͳͷǢʹͻͲȋͶȌǣʹͶ͸͸Ȃ ͹͸Ǥ ƒ‡”ƒ•  ǡ ƒ ‡‡‰Š‡Ž ǡ ‡‹• ǡ ‹ ‘Žƒ› ǡ ”‘’‡”• ǡ ‘—–‡ Ǥ ƒ”‹–‹‡ •—’’Ž‡‡–ƒ–‹‘ ƒ––‡—ƒ–‡• ›‘ ƒ”†‹ƒŽ Ž‹’‹† ƒ ——Žƒ–‹‘ ‹ Ž‘‰Ǧ Šƒ‹ ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡‘ ‘—–‹ ‡Ǥ 

(116) Š‡”‹–‡–ƒ„‹•ǤʹͲͳ͵Ǣ͵͸ȋ͸Ȍǣͻ͹͵ȂͺͳǤ ‡‡ ǡ ƒ†œ•‹‡˜ ǡ ‡Ž‡‰Š Ǥ ‘Ž‡ ‘ˆ ƒ”‹–‹‡ ƒ† ‹–• †‡”‹˜ƒ–‹˜‡• ‹ –Š‡ †‡˜‡Ž‘’‡– ƒ† ƒƒ‰‡‡–‘ˆ–›’‡ʹ†‹ƒ„‡–‡•Ǥ—–”‹ƒ„‡–‡•ǤʹͲͳͺǢͺȋͳȌǣͳȂͳͲǤ ’‹‡‡”‘‡––‡” ǡ ƒ•–‹ ǡ ‹ŽŽ‹‰Šƒ ǡ ‘””‹• ǡ ‹Œ„—”‰ ǡ ‹Ž ‡ Ǥ —””‡– ‹••—‡• ”‡‰ƒ”†‹‰ –”‡ƒ–‡– ‘ˆ ‹–‘ Š‘†”‹ƒŽ ˆƒ––› ƒ ‹† ‘š‹†ƒ–‹‘ †‹•‘”†‡”•Ǥ 

(117) Š‡”‹– ‡–ƒ„ ‹•Ǥ ʹͲͳͲǢ͵͵ȋͷȌǣͷͷͷȂ͸ͳǤ ƒŽ–‡” ǤǦƒ”‹–‹‡‹‹„‘”‡””‘”•‘ˆ‡–ƒ„‘Ž‹•ǣŠƒ–‹•–Š‡‡˜‹†‡ ‡ǫ 

(118) Š‡”‹–‡–ƒ„ ‹•ǤʹͲͲ͵Ǣʹ͸ȋʹȂ͵ȌǣͳͺͳȂͺǤ ”‹‹˜ƒ•ƒǡƒ”ƒ–ƒ•Š˜‹Ž‹ǡ™ƒƒ‰ƒ‡”ǡƒ‘ǡ‘Ž‘„‡ŽŽ‹ǡ Šƒƒ’ǡ‘ŽŽ‡ǡ ‘†‰‘”懍ǡ‘•‡  ǡ‡–‘˜‹ ǡ ƒ›ˆŽ‹ Ǥš–”ƒ ‡ŽŽ—Žƒ”ͶǯǦŠ‘•’Š‘’ƒ–‡–Š‡‹‡‹•ƒ•‘—” ‡ ˆ‘”‹–”ƒ ‡ŽŽ—Žƒ”‘‡œ›‡•›–Š‡•‹•Ǥƒ–Š‡‹‘ŽǤʹͲͳͷǢͳͳȋ—‰—•–ȌǣͳȂʹ͸Ǥ Šƒ”ƒǡ—„”ƒƒ‹ƒǡ—ǡ ”ƒǡŠ‹–‡ǡ‘ ǡ‡‡ǡ ƒ ‘™•‹Ǥ –Š‡”ƒ’‡—–‹  ƒ’’”‘ƒ Š –‘ ’ƒ–‘–Š‡ƒ–‡ ‹ƒ•‡ ƒ••‘ ‹ƒ–‡† ‡—”‘†‡‰‡‡”ƒ–‹‘Ǥ ƒ– ‘—Ǥ ʹͲͳͺǢͻȋͳȌǤ ‹‡‘

(119) ǡ‘Ž‘„‡ŽŽ‹ǡ”‹‹˜ƒ•ƒǡ†‡‹ŽŽ‹‡”•ǡ ƒƒ†ƒ ǡ ‡‘‰ǡ ‘šǡ‘Ž–Œ‡”ǡ‡’’‡”  ǡƒŠƒ›‡ǡ‹œœ‡––‘ǡ ƒ””• ǡ†‡‘‡”ǡ˜ƒ†‡”™ƒƒ‰ǡ ‡‘ǡ,—•ƒǡƒŠ‘” ǡ ‘•‡  ǡ ”œ‡• Š‹ǡ ƒ›ˆŽ‹  ǡ‹”ƒ–‹ǡ‹„‘Ǥ ‡–›ŽǦͶǯǦ’Š‘•’Š‘’ƒ–‡–Š‡‹‡‹••–ƒ„Ž‡ ‹•‡”—ƒ†’”‡˜‡–•’Š‡‘–›’‡•‹†— ‡†„›’ƒ–‘–Š‡ƒ–‡‹ƒ•‡†‡ˆ‹ ‹‡ ›Ǥ ‹‡’ǤʹͲͳ͹ ‡’ͳʹǢ͹ȋͳȌǣͳͳʹ͸ͲǤ ‹– Š‡ŽŽ ǡ ƒ—–Š‹‡”ǡ‡•‹’Ž‡ǡƒ‰ǡƒ‡”ǡ—”‡•Š‹

(120) Ǥ ‡”‡†‹–ƒ”›ƒ†ƒ “—‹”‡† †‹•‡ƒ•‡•‘ˆƒ ›ŽǦ ‘‡œ›‡‡–ƒ„‘Ž‹•Ǥ‘Ž ‡‡–‡–ƒ„ǤʹͲͲͺǢͻͶȋͳȌǣͶȂͳͷǤ ƒ‰ ǡŠƒ‘ǡƒ‰ǡƒ‰ǡ‹– Š‡ŽŽ Ǥ ‡”‡†‹–ƒ”›†‹•‡ƒ•‡•‘ˆ ‘‡œ›‡–Š‹‘‡•–‡” ‡–ƒ„‘Ž‹•Ǥ‹‘ Š‡‘ ”ƒ•ǤʹͲͳͻǢͶ͹ȋͳȌǣͳͶͻȂͷͷǤ ƒ ǡ •—ǡ”‹‰Š– ǡ‰ƒ”™ƒŽƒǡ ‘––ǡŠƒ‰ Ǥ ‡‘‡‡‰‹‡‡”‹‰—•‹‰–Š‡

(121) Ǧ. ʹ͵͹. 7.

(122) Šƒ’–‡”ͽ. ͷͶǤ. ͷͷǤ ͷ͸Ǥ ͷ͹Ǥ ͷͺǤ ͷͻǤ ͸ͲǤ. ʹ͵ͺ. ƒ•ͻ•›•–‡Ǥƒ–”‘–‘ ǤʹͲͳ͵ǢͺȋͳͳȌǣʹʹͺͳȂ͵ͲͺǤ ‘Ž–‡”• ǡ ‹ƒ’ƒ‹–‡ ǡ ƒ —‡ ǡ ‹‡œ‡Ǧ‘‹‰ ǡ ƒ––‘ ǡ ‘”–‡  ǡ ‘”˜ƒ–‘˜‹ Š ǡ ƒ‡” ǡ ‹• Š‘ˆˆ ǡ ‡”‡–‹‡” Ǥ ”ƒ•Žƒ–‹‘ƒŽ ƒ”‰‡–‡† ”‘–‡‘‹ • ”‘ˆ‹Ž‹‰ ‘ˆ ‹–‘ Š‘†”‹ƒŽ ‡”‰› ‡–ƒ„‘Ž‹  ƒ–Š™ƒ›• ‹ ‘—•‡ ƒ† —ƒ ƒ’Ž‡•Ǥ  ”‘–‡‘‡ ‡•Ǥ ʹͲͳ͸ǢͳͷȋͻȌǣ͵ʹͲͶȂͳ͵Ǥ ‹ƒ ǡ•› Š‘‰‹‘•ǡ‘—‰ǡ‹•Šƒ”–Ǥ‡–ƒ„‘ƒŽ›•–᩿ǣƒ™‡„•‡”˜‡”ˆ‘”‡–ƒ„‘Ž‘‹ †ƒ–ƒ ƒƒŽ›•‹•ƒ†‹–‡”’”‡–ƒ–‹‘ǤʹͲͲͻǢ͵͹ȋƒ›Ȍǣ͸ͷʹȂ͸ͲǤ ‹‡‡”– ǡ ‘Ž‰ƒ ǡ ‘„ƒ„‡ ǡ ”‘Š ǡ ˆ‡‹ˆ‡” ǡ ‡šŽ‡” ǡ —Ž•‡‡ Ǥ

(123) ’‡†ƒ ‡ ‡ƒ•—”‡‡– ˆ‘” ”‡ƒŽ –‹‡ †‡–‡ –‹‘ ‘ˆ ‡—”‘ƒŽ ‡ŽŽ †‡ƒ–ŠǤ  ‡—”‘• ‹ ‡–Š‘†•Ǥ ʹͲͳʹ ƒ ͳͷǢʹͲ͵ȋͳȌǣ͸ͻȂ͹͹Ǥ. — ǡ ”‡‡ ǡ”ƒˆƒŽǡ ‘†•‘Ǥ

(124) ˜‹–”‘ ‡ŽŽ—Žƒ”‘†‡Ž•‘ˆŠ—ƒŠ‡’ƒ–‹ ˆƒ––›ƒ ‹† ‡–ƒ„‘Ž‹•ǣ ‹ˆˆ‡”‡ ‡• „‡–™‡‡ —Š͹ ƒ† ‡’ ʹ ‡ŽŽ Ž‹‡• ‹ Š—ƒ ƒ† ˆ‡–ƒŽ „‘˜‹‡ —Ž–—”‹‰•‡”—ǤŠ›•‹‘Ž‡’ǤʹͲͳ͹ǢͷȋʹͶȌǣͳȂͳʹǤ –‡‡„‡”‰‡ǡ–‹ǡ‡” ‘”•–ǡƒ–ǡ‡—ˆ‡Ž†–ǡ‡Ž‘˜‘†•‹›ǡŠ—ƒǡŠ‘ ǡ ‘› ‡ǡ —–‹ŽŠ ǡ ›””‡ŽŽ Ǥ •–ƒ„Ž‹•Š‹‰ ‘”ƒŽ ‡–ƒ„‘Ž‹• ƒ† †‹ˆˆ‡”‡–‹ƒ–‹‘ ‹ Š‡’ƒ–‘ ‡ŽŽ—Žƒ” ƒ” ‹‘ƒ ‡ŽŽ•„› —Ž–—”‹‰‹ƒ†—Ž–Š—ƒ•‡”—Ǥ ‹‡’ǤʹͲͳͺ—‰͵ǢͺȋͳȌǣͳͳ͸ͺͷǤ ”ƒˆƒŽǡƒ”••‘ǡ ¡”†ˆ‡Ž†– ǡ”‹••‘ǡƒ”‹‹Ǥ—Ž–—”‹‰‘ˆ ‡’ ʹ ‡ŽŽ•™‹–ŠŠ—ƒ •‡”— ‹’”‘˜‡ –Š‡‹” ˆ— –‹‘ƒŽ‹–› ƒ† •—‹–ƒ„‹Ž‹–› ‹ •–—†‹‡• ‘ˆ Ž‹’‹† ‡–ƒ„‘Ž‹•Ǥ ‹‘ Š‹ ‹‘’Š›• –ƒǦ‘Ž‡ŽŽ‹‘Ž‹’‹†•ǤʹͲͳ͸Ǣͳͺ͸ͳȋͳȌǣͷͳȂͻǤ ƒƒ‡œ ǡƒ”‘ǡ”‹ƒ†ǡ‡Š‘†– ǡ—’Žƒ

(125) ǡ—‹’‡”• ǡ ‡—›‡”ǡŽƒ˜‡›ǡ–ƒ‡Ž•Ǥ Š‡ Š—ƒ Š‡’ƒ–‘ ›–‡ ‡ŽŽ Ž‹‡•

(126)  ƒ† ‡’ƒ ǣ ‘†‡Ž• –‘ •–—†› ‰Ž— ‘•‡ǡ Ž‹’‹† ƒ† Ž‹’‘’”‘–‡‹‡–ƒ„‘Ž‹•Ǥ” ŠŠ›•‹‘Ž‹‘ Š‡ǤʹͲͳʹǢͳͳͺȋƒ” ŠȌǣͳͲʹȂͳͳǤ.

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