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ΠΠΠ’ΠΠ ΠΠΠΠΠΠ’Π« ΠΠΠΠ ΠΠΠΠΠ ΠΠΠΠ‘ΠΠΠ§ΠΠΠΠ― Π ΠΠΠΠΠΠ Π‘ Π£Π§ΠΠ’ΠΠ ΠΠ’Π ΠΠ‘ΠΠΠΠΠ Π‘ΠΠΠ¦ΠΠΠΠΠΠΠ¦ΠΠ
Π ΡΡΠ»ΠΎΠ²ΠΈΡΡ
ΡΠΈΡΡΠΎΠ²ΠΈΠ·Π°ΡΠΈΠΈ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ, Π½Π΅ΠΈΠ·Π±Π΅ΠΆΠ½ΠΎ Π²Π»ΠΈΡΡΡΠ΅ΠΉ Π½Π° ΡΡΠ½ΠΎΠΊ ΡΡΡΠ΄Π°, Π½Π΅ΠΎΠ±Ρ
ΠΎΠ΄ΠΈΠΌΠΎ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ ΠΊΠ°Π΄ΡΠΎΠ²ΠΎΠ³ΠΎ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΡ ΠΊΠ°ΠΆΠ΄ΠΎΠ³ΠΎ ΡΠ΅Π³ΠΈΠΎΠ½Π° ΡΡΡΠ°Π½Ρ Ρ ΡΡΠ΅ΡΠΎΠΌ Π΅Π³ΠΎ ΡΠΏΠ΅ΡΠΈΠ°Π»ΠΈΠ·Π°ΡΠΈΠΈ β ΠΏΡΠ΅Π²Π°Π»ΠΈΡΠΎΠ²Π°Π½ΠΈΡ Π² ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠ΅ ΡΠ΅Π»ΡΡΠΊΠΎΠ³ΠΎ Ρ
ΠΎΠ·ΡΠΉΡΡΠ²Π°, ΠΏΡΠΎΠΌΡΡΠ»Π΅Π½Π½ΠΎΡΡΠΈ ΠΈΠ»ΠΈ ΠΈΠ½ΡΡ
Π²ΠΈΠ΄ΠΎΠ² Π΄Π΅ΡΡΠ΅Π»ΡΠ½ΠΎΡΡΠΈ. Π¦Π΅Π»ΡΡ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΡΠ²Π»ΡΠ»ΠΎΡΡ ΠΎΠ±ΠΎΡΠ½ΠΎΠ²Π°Π½ΠΈΠ΅ Π΄Π΅ΡΠ΅ΡΠΌΠΈΠ½Π°Π½Ρ ΠΊΠ°Π΄ΡΠΎΠ²ΠΎΠ³ΠΎ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΡ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ ΡΠ΅Π³ΠΈΠΎΠ½ΠΎΠ² Ρ ΡΡΠ΅ΡΠΎΠΌ Π΄ΠΎΠΌΠΈΠ½ΠΈΡΠΎΠ²Π°Π½ΠΈΡ Π²ΠΈΠ΄ΠΎΠ² ΡΠΊΠΎΠ½ΠΎΠΌΠΈΡΠ΅ΡΠΊΠΎΠΉ Π΄Π΅ΡΡΠ΅Π»ΡΠ½ΠΎΡΡΠΈ. Π ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΠΎΡΠ½ΠΎΠ²Π½ΠΎΠ³ΠΎ ΠΌΠ΅ΡΠΎΠ΄Π° ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ ΡΡΠ°ΡΠΈΡΡΠΈΡΠ΅ΡΠΊΠΈΠΉ Π°Π½Π°Π»ΠΈΠ· Π΄Π°Π½Π½ΡΡ
, ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½Ρ ΠΌΠ΅ΡΠΎΠ΄Ρ ΡΡΠ°Π²Π½Π΅Π½ΠΈΡ ΠΈ ΠΏΡΠΈΡΠΈΠ½Π½ΠΎ-ΡΠ»Π΅Π΄ΡΡΠ²Π΅Π½Π½ΡΠΉ Π°Π½Π°Π»ΠΈΠ·. ΠΡΡΠ²Π»Π΅Π½Ρ Π·Π½Π°ΡΠΈΠΌΡΠ΅ Π΄Π΅ΡΠ΅ΡΠΌΠΈΠ½Π°Π½ΡΡ ΠΊΠ°Π΄ΡΠΎΠ²ΠΎΠ³ΠΎ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΡ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ ΡΠ΅Π³ΠΈΠΎ-
Π½Π°: ΡΠΈΡΡΠ΅ΠΌΠ° ΡΠΏΡΠ°Π²Π»Π΅Π½ΠΈΡ, Π½Π°Π»ΠΈΡΠΈΠ΅ ΠΈ Π΄Π²ΠΈΠΆΠ΅Π½ΠΈΠ΅ ΡΡΡΠ΄ΠΎΠ²ΡΡ
ΡΠ΅ΡΡΡΡΠΎΠ², ΡΠΈΡΡΠ΅ΠΌΠ° ΠΏΡΠΎΡΠ΅ΡΡΠΈΠΎΠ½Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΡ ΠΈ, Π² ΡΠ°ΡΡΠ½ΠΎΡΡΠΈ, ΡΠΎΠ»Ρ Π² Π½Π΅ΠΉ ΠΌΠ΅ΡΡΠ½ΡΡ
ΡΠ½ΠΈΠ²Π΅ΡΡΠΈΡΠ΅ΡΠΎΠ². ΠΡΠ΅Π΄Π»ΠΎΠΆΠ΅Π½ΠΎ Π²Π½Π΅Π΄ΡΠ΅Π½ΠΈΠ΅ Π² Π΄Π΅ΡΡΠ΅Π»ΡΠ½ΠΎΡΡΡ ΡΠ΅Π³ΠΈΠΎΠ½Π°Π»ΡΠ½ΡΡ
ΠΎΡΠ³Π°Π½ΠΎΠ² Π²Π»Π°ΡΡΠΈ Π°Π²ΡΠΎΠΌΠ°ΡΠΈΠ·ΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠΉ ΠΈΠ½ΡΠ΅Π»Π»Π΅ΠΊΡΡΠ°Π»ΡΠ½ΠΎΠΉ ΡΠΈΡΡΠ΅ΠΌΡ ΠΏΠΎΠ΄Π΄Π΅ΡΠΆΠΊΠΈ ΠΏΡΠΈΠ½ΡΡΠΈΡ ΡΠ΅ΡΠ΅Π½ΠΈΠΉ (ΠΠΠ‘ΠΠΠ ) ΠΈ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»Π΅Π½ ΠΌΠ΅ΡΠΎΠ΄ΠΈΡΠ΅ΡΠΊΠΈΠΉ ΠΏΠΎΠ΄Ρ
ΠΎΠ΄ ΠΊ ΡΠΏΠΎΡΠΎΠ±Π°ΠΌ ΠΏΠΎΠ±Π»ΠΎΡΠ½ΠΎΠΉ ΠΎΡΠ³Π°Π½ΠΈΠ·Π°ΡΠΈΠΈ Ρ
ΡΠ°Π½ΠΈΠ»ΠΈΡΠ° Π΄Π°Π½Π½ΡΡ
Π² Π½Π΅ΠΉ (Π½Π° ΠΏΡΠΈΠΌΠ΅ΡΠ΅ ΠΡΠ΅Π½Π±ΡΡΠ³ΡΠΊΠΎΠΉ ΠΎΠ±Π»Π°ΡΡΠΈ). ΠΡΠΌΠ΅ΡΠ΅Π½ΠΎ, ΡΡΠΎ Π²Π΅Π΄Π΅ΡΡΡ ΡΠ°Π±ΠΎΡΠ° Π½Π°Π΄ Π°ΡΡ
ΠΈΡΠ΅ΠΊΡΡΡΠΎΠΉ ΠΈ Π°Π»Π³ΠΎΡΠΈΡΠΌΠΎΠΌ ΠΠΠ‘ΠΠΠ , ΠΊΠΎΡΠΎΡΡΠ΅ ΠΌΠΎΠ³ΡΡ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°ΡΡΡΡ Π½Π΅ ΡΠΎΠ»ΡΠΊΠΎ Π΄Π»Ρ ΡΠΏΡΠ°Π²Π»Π΅Π½ΠΈΡ ΠΊΠ°Π΄ΡΠΎΠ²ΡΠΌ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΠ΅ΠΌ, Π½ΠΎ ΠΈ Π΄Π»Ρ ΠΈΠ·ΡΡΠ΅Π½ΠΈΡ ΠΈ ΠΏΡΠΎΠ³Π½ΠΎΠ·ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΡΠΈΡΠΎΠΊΠΎΠ³ΠΎ ΡΠΏΠ΅ΠΊΡΡΠ° ΡΠ°ΠΊΡΠΎΡΠΎΠ² ΡΠ°Π·Π²ΠΈΡΠΈΡ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ ΡΠ΅Π³ΠΈΠΎΠ½ΠΎΠ² Π ΠΎΡΡΠΈΠΈ. Π ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ΅ Π°ΠΏΡΠΎΠ±Π°ΡΠΈΠΈ ΡΠ΄Π΅Π»Π°Π½Ρ Π²ΡΠ²ΠΎΠ΄Ρ: Π² ΠΡΠ΅Π½Π±ΡΡΠ³ΡΠΊΠΎΠΉ ΠΎΠ±Π»Π°ΡΡΠΈ Ρ 2014 Π³. ΠΏΡΠΎΠΈΡΡ
ΠΎΠ΄ΠΈΡ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΠ΅ ΡΠΈΡΠ»Π΅Π½Π½ΠΎΡΡΠΈ Π½Π°ΡΠ΅Π»Π΅Π½ΠΈΡ Ρ ΠΎΠΏΠ΅ΡΠ΅ΠΆΠ°ΡΡΠΈΠΌ ΡΠΌΠ΅Π½ΡΡΠ΅Π½ΠΈΠ΅ΠΌ Π΄ΠΎΠ»ΠΈ ΡΠ΅Π»ΡΡΠΊΠΎΠ³ΠΎ Π½Π°ΡΠ΅Π»Π΅Π½ΠΈΡ ΠΎΡΠ½ΠΎΡΠΈΡΠ΅Π»ΡΠ½ΠΎ Π³ΠΎΡΠΎΠ΄ΡΠΊΠΎΠ³ΠΎ (ΡΡΠΎ Ρ ΡΡΠ΅ΡΠΎΠΌ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΡΠ΅ΡΠΊΠΎΠΉ ΡΠΏΠ΅ΡΠΈΠ°Π»ΠΈΠ·Π°ΡΠΈΠΈ ΡΠ΅Π³ΠΈΠΎΠ½Π° Π½Π΅Π³Π°ΡΠΈΠ²Π½ΠΎ ΠΎΡΡΠ°ΠΆΠ°Π΅ΡΡΡ Π½Π° Π²ΠΎΡΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΡΡΠ²Π΅ ΡΡΡΠ΄ΠΎΠ²ΡΡ
ΡΠ΅ΡΡΡΡΠΎΠ²), Π½ΠΈΠ·ΠΊΠΈ ΡΠ΅ΠΌΠΏΡ ΡΠ΅Π°Π»ΠΈΠ·Π°ΡΠΈΠΈ ΠΈΠ½Π½ΠΎΠ²Π°ΡΠΈΠΉ, Π²ΠΎΠΏΡΠΎΡ ΡΠ°Π·Π²ΠΈΡΠΈΡ Π½Π°ΡΠΊΠΎΠ΅ΠΌΠΊΠΈΡ
ΠΎΡΡΠ°ΡΠ»Π΅ΠΉ ΡΡΠΎΠΈΡ Π΄ΠΎΡΡΠ°ΡΠΎΡΠ½ΠΎ ΠΎΡΡΡΠΎ, Π² ΡΠ²ΡΠ·ΠΈ Ρ ΡΠ΅ΠΌ Π½Π΅ΠΎΠ±Ρ
ΠΎΠ΄ΠΈΠΌΠΎ Π°ΠΊΡΠΈΠ²ΠΈΠ·ΠΈΡΠΎΠ²Π°ΡΡ ΠΏΠΎΠ΄Π³ΠΎΡΠΎΠ²ΠΊΡ Π²ΡΡΠΎΠΊΠΎΠΊΠ²Π°Π»ΠΈΡΠΈΡΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
ΡΠΏΠ΅ΡΠΈΠ°Π»ΠΈΡΡΠΎΠ² (ΠΏΡΠ΅ΠΆΠ΄Π΅ Π²ΡΠ΅Π³ΠΎ Π² ΡΠ΅Π³ΠΈΠΎΠ½Π°Π»ΡΠ½ΡΡ
ΡΠ½ΠΈΠ²Π΅ΡΡΠΈΡΠ΅ΡΠ°Ρ
), Π²Π»Π°Π΄Π΅ΡΡΠΈΡ
Π½Π΅ΠΎΠ±Ρ
ΠΎΠ΄ΠΈΠΌΡΠΌΠΈ ΠΊΠΎΠΌΠΏΠ΅ΡΠ΅Π½ΡΠΈΡΠΌΠΈ Π΄Π»Ρ ΡΠ°Π±ΠΎΡΡ Π² ΡΡΠ»ΠΎΠ²ΠΈΡΡ
ΡΠΈΡΡΠΎΠ²ΠΈΠ·Π°ΡΠΈΠΈ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ. ΠΠ°ΡΠ΅ΡΠΈΠ°Π»Ρ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»ΡΡΡ ΠΈΠ½ΡΠ΅ΡΠ΅Ρ Π΄Π»Ρ ΡΡΠ΅Π½ΡΡ
ΠΈ ΡΠΏΠ΅ΡΠΈΠ°Π»ΠΈΡΡΠΎΠ² Π² ΠΎΠ±Π»Π°ΡΡΠΈ ΡΠ°Π·Π²ΠΈΡΠΈΡ ΡΠ΅Π»ΠΎΠ²Π΅ΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΠΊΠ°ΠΏΠΈΡΠ°Π»Π° ΠΈ ΠΌΠΎΠ³ΡΡ Π±ΡΡΡ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½Ρ ΠΏΡΠΈ ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠ΅ ΠΌΠ΅Ρ Π³ΠΎΡΡΠ΄Π°ΡΡΡΠ²Π΅Π½Π½ΠΎΠΉ ΠΏΠΎΠ»ΠΈΡΠΈΠΊΠΈ ΠΏΠΎ ΠΊΠ°Π΄ΡΠΎΠ²ΠΎΠΌΡ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΡ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ ΡΠ΅Π³ΠΈΠΎΠ½Π°
ΠΠΠ’ΠΠ ΠΠΠΠΠΠ’Π« ΠΠΠΠ ΠΠΠΠΠ ΠΠΠΠ‘ΠΠΠ§ΠΠΠΠ― Π ΠΠΠΠΠΠ Π‘ Π£Π§ΠΠ’ΠΠ ΠΠ’Π ΠΠ‘ΠΠΠΠΠ Π‘ΠΠΠ¦ΠΠΠΠΠΠΠ¦ΠΠ
Π ΡΡΠ»ΠΎΠ²ΠΈΡΡ
ΡΠΈΡΡΠΎΠ²ΠΈΠ·Π°ΡΠΈΠΈ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ, Π½Π΅ΠΈΠ·Π±Π΅ΠΆΠ½ΠΎ Π²Π»ΠΈΡΡΡΠ΅ΠΉ Π½Π° ΡΡΠ½ΠΎΠΊ ΡΡΡΠ΄Π°, Π½Π΅ΠΎΠ±Ρ
ΠΎΠ΄ΠΈΠΌΠΎ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ ΠΊΠ°Π΄ΡΠΎΠ²ΠΎΠ³ΠΎ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΡ ΠΊΠ°ΠΆΠ΄ΠΎΠ³ΠΎ ΡΠ΅Π³ΠΈΠΎΠ½Π° ΡΡΡΠ°Π½Ρ Ρ ΡΡΠ΅ΡΠΎΠΌ Π΅Π³ΠΎ ΡΠΏΠ΅ΡΠΈΠ°Π»ΠΈΠ·Π°ΡΠΈΠΈ β ΠΏΡΠ΅Π²Π°Π»ΠΈΡΠΎΠ²Π°Π½ΠΈΡ Π² ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠ΅ ΡΠ΅Π»ΡΡΠΊΠΎΠ³ΠΎ Ρ
ΠΎΠ·ΡΠΉΡΡΠ²Π°, ΠΏΡΠΎΠΌΡΡΠ»Π΅Π½Π½ΠΎΡΡΠΈ ΠΈΠ»ΠΈ ΠΈΠ½ΡΡ
Π²ΠΈΠ΄ΠΎΠ² Π΄Π΅ΡΡΠ΅Π»ΡΠ½ΠΎΡΡΠΈ. Π¦Π΅Π»ΡΡ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΡΠ²Π»ΡΠ»ΠΎΡΡ ΠΎΠ±ΠΎΡΠ½ΠΎΠ²Π°Π½ΠΈΠ΅ Π΄Π΅ΡΠ΅ΡΠΌΠΈΠ½Π°Π½Ρ ΠΊΠ°Π΄ΡΠΎΠ²ΠΎΠ³ΠΎ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΡ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ ΡΠ΅Π³ΠΈΠΎΠ½ΠΎΠ² Ρ ΡΡΠ΅ΡΠΎΠΌ Π΄ΠΎΠΌΠΈΠ½ΠΈΡΠΎΠ²Π°Π½ΠΈΡ Π²ΠΈΠ΄ΠΎΠ² ΡΠΊΠΎΠ½ΠΎΠΌΠΈΡΠ΅ΡΠΊΠΎΠΉ Π΄Π΅ΡΡΠ΅Π»ΡΠ½ΠΎΡΡΠΈ. Π ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΠΎΡΠ½ΠΎΠ²Π½ΠΎΠ³ΠΎ ΠΌΠ΅ΡΠΎΠ΄Π° ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ ΡΡΠ°ΡΠΈΡΡΠΈΡΠ΅ΡΠΊΠΈΠΉ Π°Π½Π°Π»ΠΈΠ· Π΄Π°Π½Π½ΡΡ
, ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½Ρ ΠΌΠ΅ΡΠΎΠ΄Ρ ΡΡΠ°Π²Π½Π΅Π½ΠΈΡ ΠΈ ΠΏΡΠΈΡΠΈΠ½Π½ΠΎ-ΡΠ»Π΅Π΄ΡΡΠ²Π΅Π½Π½ΡΠΉ Π°Π½Π°Π»ΠΈΠ·. ΠΡΡΠ²Π»Π΅Π½Ρ Π·Π½Π°ΡΠΈΠΌΡΠ΅ Π΄Π΅ΡΠ΅ΡΠΌΠΈΠ½Π°Π½ΡΡ ΠΊΠ°Π΄ΡΠΎΠ²ΠΎΠ³ΠΎ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΡ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ ΡΠ΅Π³ΠΈΠΎ-
Π½Π°: ΡΠΈΡΡΠ΅ΠΌΠ° ΡΠΏΡΠ°Π²Π»Π΅Π½ΠΈΡ, Π½Π°Π»ΠΈΡΠΈΠ΅ ΠΈ Π΄Π²ΠΈΠΆΠ΅Π½ΠΈΠ΅ ΡΡΡΠ΄ΠΎΠ²ΡΡ
ΡΠ΅ΡΡΡΡΠΎΠ², ΡΠΈΡΡΠ΅ΠΌΠ° ΠΏΡΠΎΡΠ΅ΡΡΠΈΠΎΠ½Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΡ ΠΈ, Π² ΡΠ°ΡΡΠ½ΠΎΡΡΠΈ, ΡΠΎΠ»Ρ Π² Π½Π΅ΠΉ ΠΌΠ΅ΡΡΠ½ΡΡ
ΡΠ½ΠΈΠ²Π΅ΡΡΠΈΡΠ΅ΡΠΎΠ². ΠΡΠ΅Π΄Π»ΠΎΠΆΠ΅Π½ΠΎ Π²Π½Π΅Π΄ΡΠ΅Π½ΠΈΠ΅ Π² Π΄Π΅ΡΡΠ΅Π»ΡΠ½ΠΎΡΡΡ ΡΠ΅Π³ΠΈΠΎΠ½Π°Π»ΡΠ½ΡΡ
ΠΎΡΠ³Π°Π½ΠΎΠ² Π²Π»Π°ΡΡΠΈ Π°Π²ΡΠΎΠΌΠ°ΡΠΈΠ·ΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠΉ ΠΈΠ½ΡΠ΅Π»Π»Π΅ΠΊΡΡΠ°Π»ΡΠ½ΠΎΠΉ ΡΠΈΡΡΠ΅ΠΌΡ ΠΏΠΎΠ΄Π΄Π΅ΡΠΆΠΊΠΈ ΠΏΡΠΈΠ½ΡΡΠΈΡ ΡΠ΅ΡΠ΅Π½ΠΈΠΉ (ΠΠΠ‘ΠΠΠ ) ΠΈ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»Π΅Π½ ΠΌΠ΅ΡΠΎΠ΄ΠΈΡΠ΅ΡΠΊΠΈΠΉ ΠΏΠΎΠ΄Ρ
ΠΎΠ΄ ΠΊ ΡΠΏΠΎΡΠΎΠ±Π°ΠΌ ΠΏΠΎΠ±Π»ΠΎΡΠ½ΠΎΠΉ ΠΎΡΠ³Π°Π½ΠΈΠ·Π°ΡΠΈΠΈ Ρ
ΡΠ°Π½ΠΈΠ»ΠΈΡΠ° Π΄Π°Π½Π½ΡΡ
Π² Π½Π΅ΠΉ (Π½Π° ΠΏΡΠΈΠΌΠ΅ΡΠ΅ ΠΡΠ΅Π½Π±ΡΡΠ³ΡΠΊΠΎΠΉ ΠΎΠ±Π»Π°ΡΡΠΈ). ΠΡΠΌΠ΅ΡΠ΅Π½ΠΎ, ΡΡΠΎ Π²Π΅Π΄Π΅ΡΡΡ ΡΠ°Π±ΠΎΡΠ° Π½Π°Π΄ Π°ΡΡ
ΠΈΡΠ΅ΠΊΡΡΡΠΎΠΉ ΠΈ Π°Π»Π³ΠΎΡΠΈΡΠΌΠΎΠΌ ΠΠΠ‘ΠΠΠ , ΠΊΠΎΡΠΎΡΡΠ΅ ΠΌΠΎΠ³ΡΡ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°ΡΡΡΡ Π½Π΅ ΡΠΎΠ»ΡΠΊΠΎ Π΄Π»Ρ ΡΠΏΡΠ°Π²Π»Π΅Π½ΠΈΡ ΠΊΠ°Π΄ΡΠΎΠ²ΡΠΌ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΠ΅ΠΌ, Π½ΠΎ ΠΈ Π΄Π»Ρ ΠΈΠ·ΡΡΠ΅Π½ΠΈΡ ΠΈ ΠΏΡΠΎΠ³Π½ΠΎΠ·ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΡΠΈΡΠΎΠΊΠΎΠ³ΠΎ ΡΠΏΠ΅ΠΊΡΡΠ° ΡΠ°ΠΊΡΠΎΡΠΎΠ² ΡΠ°Π·Π²ΠΈΡΠΈΡ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ ΡΠ΅Π³ΠΈΠΎΠ½ΠΎΠ² Π ΠΎΡΡΠΈΠΈ. Π ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ΅ Π°ΠΏΡΠΎΠ±Π°ΡΠΈΠΈ ΡΠ΄Π΅Π»Π°Π½Ρ Π²ΡΠ²ΠΎΠ΄Ρ: Π² ΠΡΠ΅Π½Π±ΡΡΠ³ΡΠΊΠΎΠΉ ΠΎΠ±Π»Π°ΡΡΠΈ Ρ 2014 Π³. ΠΏΡΠΎΠΈΡΡ
ΠΎΠ΄ΠΈΡ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΠ΅ ΡΠΈΡΠ»Π΅Π½Π½ΠΎΡΡΠΈ Π½Π°ΡΠ΅Π»Π΅Π½ΠΈΡ Ρ ΠΎΠΏΠ΅ΡΠ΅ΠΆΠ°ΡΡΠΈΠΌ ΡΠΌΠ΅Π½ΡΡΠ΅Π½ΠΈΠ΅ΠΌ Π΄ΠΎΠ»ΠΈ ΡΠ΅Π»ΡΡΠΊΠΎΠ³ΠΎ Π½Π°ΡΠ΅Π»Π΅Π½ΠΈΡ ΠΎΡΠ½ΠΎΡΠΈΡΠ΅Π»ΡΠ½ΠΎ Π³ΠΎΡΠΎΠ΄ΡΠΊΠΎΠ³ΠΎ (ΡΡΠΎ Ρ ΡΡΠ΅ΡΠΎΠΌ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΡΠ΅ΡΠΊΠΎΠΉ ΡΠΏΠ΅ΡΠΈΠ°Π»ΠΈΠ·Π°ΡΠΈΠΈ ΡΠ΅Π³ΠΈΠΎΠ½Π° Π½Π΅Π³Π°ΡΠΈΠ²Π½ΠΎ ΠΎΡΡΠ°ΠΆΠ°Π΅ΡΡΡ Π½Π° Π²ΠΎΡΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΡΡΠ²Π΅ ΡΡΡΠ΄ΠΎΠ²ΡΡ
ΡΠ΅ΡΡΡΡΠΎΠ²), Π½ΠΈΠ·ΠΊΠΈ ΡΠ΅ΠΌΠΏΡ ΡΠ΅Π°Π»ΠΈΠ·Π°ΡΠΈΠΈ ΠΈΠ½Π½ΠΎΠ²Π°ΡΠΈΠΉ, Π²ΠΎΠΏΡΠΎΡ ΡΠ°Π·Π²ΠΈΡΠΈΡ Π½Π°ΡΠΊΠΎΠ΅ΠΌΠΊΠΈΡ
ΠΎΡΡΠ°ΡΠ»Π΅ΠΉ ΡΡΠΎΠΈΡ Π΄ΠΎΡΡΠ°ΡΠΎΡΠ½ΠΎ ΠΎΡΡΡΠΎ, Π² ΡΠ²ΡΠ·ΠΈ Ρ ΡΠ΅ΠΌ Π½Π΅ΠΎΠ±Ρ
ΠΎΠ΄ΠΈΠΌΠΎ Π°ΠΊΡΠΈΠ²ΠΈΠ·ΠΈΡΠΎΠ²Π°ΡΡ ΠΏΠΎΠ΄Π³ΠΎΡΠΎΠ²ΠΊΡ Π²ΡΡΠΎΠΊΠΎΠΊΠ²Π°Π»ΠΈΡΠΈΡΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
ΡΠΏΠ΅ΡΠΈΠ°Π»ΠΈΡΡΠΎΠ² (ΠΏΡΠ΅ΠΆΠ΄Π΅ Π²ΡΠ΅Π³ΠΎ Π² ΡΠ΅Π³ΠΈΠΎΠ½Π°Π»ΡΠ½ΡΡ
ΡΠ½ΠΈΠ²Π΅ΡΡΠΈΡΠ΅ΡΠ°Ρ
), Π²Π»Π°Π΄Π΅ΡΡΠΈΡ
Π½Π΅ΠΎΠ±Ρ
ΠΎΠ΄ΠΈΠΌΡΠΌΠΈ ΠΊΠΎΠΌΠΏΠ΅ΡΠ΅Π½ΡΠΈΡΠΌΠΈ Π΄Π»Ρ ΡΠ°Π±ΠΎΡΡ Π² ΡΡΠ»ΠΎΠ²ΠΈΡΡ
ΡΠΈΡΡΠΎΠ²ΠΈΠ·Π°ΡΠΈΠΈ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ. ΠΠ°ΡΠ΅ΡΠΈΠ°Π»Ρ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»ΡΡΡ ΠΈΠ½ΡΠ΅ΡΠ΅Ρ Π΄Π»Ρ ΡΡΠ΅Π½ΡΡ
ΠΈ ΡΠΏΠ΅ΡΠΈΠ°Π»ΠΈΡΡΠΎΠ² Π² ΠΎΠ±Π»Π°ΡΡΠΈ ΡΠ°Π·Π²ΠΈΡΠΈΡ ΡΠ΅Π»ΠΎΠ²Π΅ΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΠΊΠ°ΠΏΠΈΡΠ°Π»Π° ΠΈ ΠΌΠΎΠ³ΡΡ Π±ΡΡΡ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½Ρ ΠΏΡΠΈ ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠ΅ ΠΌΠ΅Ρ Π³ΠΎΡΡΠ΄Π°ΡΡΡΠ²Π΅Π½Π½ΠΎΠΉ ΠΏΠΎΠ»ΠΈΡΠΈΠΊΠΈ ΠΏΠΎ ΠΊΠ°Π΄ΡΠΎΠ²ΠΎΠΌΡ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΡ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ ΡΠ΅Π³ΠΈΠΎΠ½Π°
In vitro modeling of tumor interclonal interactions using breast cancer cell lines
In the setting of limited resources, natural selection begins to occur between tumor clones. An experimental model of in vitro tumor heterogeneity would allow us to evaluate various types of biological interactions arising from the joint cultivation of phenotypically different tumor clones. Aim: To study the peculiarities of ecological relationships of breast cancer (BC) cell lines MCF-7, BT-474 and MDA-MD-231 under co-culturing conditions. Materials and Methods: Three BC cell lines: luminal A β MCF-7, luminal B β BT-474 and triple-negative β MDA-MD-231 were co-cultured pairwise. Immunocytochemistry was used to differentiate the cell lines in the wells. The effect of the cell-free culture medium on the growth rate of the alternate cell line in the pair was also evaluated. Results: It was shown that when BT-474 cells were co-cultured with MCF-7 and BT-474 cells were co-cultured with MDA-MD-231, two types of ecological interactions could be observed: commensalism and amensalism, respectively. While the cells do not interact with each other in contact, the supernatants of single cultures of MCF-7 and MDAMD-231 exert the same effect on BT-474 as co-cultivation of BT-474 with these cells. Conclusions: The paracrine mechanism of intercellular interaction between different human BC cell lines has been demonstrated. The models used in population ecology can be applicable to identify the types of interaction between cell lines
Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial
Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials.
Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.
Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen.
Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049
Slowly Reducible Genetically Encoded Green Fluorescent Indicator for In Vivo and Ex Vivo Visualization of Hydrogen Peroxide
Hydrogen peroxide (H2O2) plays an important role in modulating cell signaling and homeostasis in live organisms. The HyPer family of genetically encoded indicators allows the visualization of H2O2 dynamics in live cells within a limited field of view. The visualization of H2O2 within a whole organism with a single cell resolution would benefit from a slowly reducible fluorescent indicator that integrates the H2O2 concentration over desired time scales. This would enable post hoc optical readouts in chemically fixed samples. Herein, we report the development and characterization of NeonOxIrr, a genetically encoded green fluorescent indicator, which rapidly increases fluorescence brightness upon reaction with H2O2, but has a low reduction rate. NeonOxIrr is composed of circularly permutated mNeonGreen fluorescent protein fused to the truncated OxyR transcription factor isolated from E. coli. When compared in vitro to a standard in the field, HyPer3 indicator, NeonOxIrr showed 5.9-fold higher brightness, 15-fold faster oxidation rate, 5.9-fold faster chromophore maturation, similar intensiometric contrast (2.8-fold), 2-fold lower photostability, and significantly higher pH stability both in reduced (pKa of 5.9 vs. ≥7.6) and oxidized states (pKa of 5.9 vs.≥ 7.9). When expressed in the cytosol of HEK293T cells, NeonOxIrr demonstrated a 2.3-fold dynamic range in response to H2O2 and a 44 min reduction half-time, which were 1.4-fold lower and 7.6-fold longer than those for HyPer3. We also demonstrated and characterized the NeonOxIrr response to H2O2 when the sensor was targeted to the matrix and intermembrane space of the mitochondria, nucleus, cell membranes, peroxisomes, Golgi complex, and endoplasmic reticulum of HEK293T cells. NeonOxIrr could reveal endogenous reactive oxygen species (ROS) production in HeLa cells induced with staurosporine but not with thapsigargin or epidermal growth factor. In contrast to HyPer3, NeonOxIrr could visualize optogenetically produced ROS in HEK293T cells. In neuronal cultures, NeonOxIrr preserved its high 3.2-fold dynamic range to H2O2 and slow 198 min reduction half-time. We also demonstrated in HeLa cells that NeonOxIrr preserves a 1.7-fold ex vivo dynamic range to H2O2 upon alkylation with N-ethylmaleimide followed by paraformaldehyde fixation. The same alkylation-fixation procedure in the presence of NP-40 detergent allowed ex vivo detection of H2O2 with 1.5-fold contrast in neuronal cultures and in the cortex of the mouse brain. The slowly reducible H2O2 indicator NeonOxIrr can be used for both the in vivo and ex vivo visualization of ROS. Expanding the family of fixable indicators may be a promising strategy to visualize biological processes at a single cell resolution within an entire organism