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Historia Austrii – tereny obecnej Austrii były zamieszkane w okresie starożytności przez plemiona celtyckie. W I wieku p.n.e. większość jej obszaru zostało podbite przez Cesarstwo Rzymskie, następnie Austria była częścią Cesarstwa zachodniorzymskiego. W średniowieczu była częścią I Rzeszy niemieckiej. Najdłużej, bo od drugiej połowy XIII wieku do 1918 roku rządzona była przez dynastię Habsburgów. W latach 1867-1918 wchodziła w skład Austro Węgier. Od rozpadu monarchii Austro-Węgier jest republiką, od 1995 roku członek Unii Europejskiej.

Celtowie i Rzymianie na ziemiach austriackich
Początki osadnictwa sięgają na tym obszarze 5000 lat p.n.e. W starożytności obszar dzisiejszej Austrii były zamieszkiwane przez plemiona celtyckie około 500-200 p.n.e., które tworzyły tutaj swoje państwo zwane królestwem Noricum. W czasie podbojów rzymskich obszar wszedł bezpośrednio pod panowanie cesarstwa w 15 p.n.e. W 41 n.e. rzymski cesarz Klaudiusz nadał temu obszarowi status prowincji rzymskiej, którą nazwano Noricum. Stolicą prowincji zostało miasto Virunum. Rzymianie założyli w miejscu dzisiejszej stolicy Austrii, obóz warowny nazwany Vindoboną.

Średniowiecze
W czasie upadku cesarstwa co zapoczątkowało Wielką wędrówkę ludów w IV wieku n. e., terytorium Austrii zostało zajęte przez Bawarów, następnie Awarów. Obszar, co najmniej, obecnej Dolnej Austrii był zasiedlony przez Słowian, o czym świadczy do dziś toponimia. W 778 została utworzona Marchia Wschodnia (Ostmark) w państwie frankijskim Karola Wielkiego, co zapoczątkowało chrystianizację tych ziem. Po upadku monarchii Karola Wielkiego, obszar ten przypadł na mocy traktatu w Verdun w 843 roku państwu wschodniofrankijskiemu Ludwika Niemieckiego syna Ludwika I Pobożnego wnuka Karola Wielkiego.

W 909 roku obszar Austrii został najechany przez Węgrów. Po ich klęsce w bitwie na Lechowym Polu w 955 roku ziemie Marchii Wschodniej ustabilizowały się. Od ok. 975/976 Marchią zaczęli władać Babenbergowie którzy zostali mianowani władcami Marchii Wschodniej.

Pierwszy władca z tej dynastii, Leopold I Babenberg zmarł w 994 roku. Jego następcą został Henryk I. Babenbergowie rządzili Austrią do 1246 r. Do 1276 Austrią rządził Przemysł Ottokar II z dynastii czeskich Przemyślidów, a po nim władzę uzyskał Rudolf I z dynastii Habsburgów.

Za rządów dynastii Babenbergów Austria zaliczana była do mniej znaczących państw Europy Środkowej. Zdobyli na krótko wpływy w pobliskiej Bawarii w latach 1139–1156, uzyskali również tytuł książęcy dla swojej władzy w Austrii w 1156 roku, który nadał Henrykowi II Fryderyk Barbarossa. Prowadzili swoją politykę dynastyczną o czym świadczy fakt wydania za mąż córki Leopolda III Świętego za Władysława Wygnańca księcia polskiego z dynastii Piastów, syna Bolesława Krzywoustego i Zbysławy Kijowskiej z ruskiej dynastii Rurykowiczów pomiędzy 1125 rokiem a 1127 rokiem. Małżeństwo było zawarte w celach politycznych, bowiem wzmocniło opozycję do niemieckiego rodu Hohenstaufów. Władcy austriaccy brali również udział w wyprawach krzyżowych. Leopold VI Sławny uczestniczył w krucjacie przeciwko Albigensom i V krucjacie. Babenbergowie za jego rządów byli pośrednikami w sporze Fryderyka II z papieżem. Jego następcą był ostatni z Babenbergów Fryderyk II Bitny syn Leopolda VI i bizantyjskiej księżniczki Teodory Angeliny. Prowadził wojny z Czechami, Węgrami i przejściowo z Fryderykiem II. Po jego śmierci w 1246 roku podczas bitwy nad rzeką Litawą rozpoczęły się walki o panowanie w Austrii, którą od 1276 roku rządził przedstawiciel czeskiej dynastii Przemyślidów Przemysł Ottokar II. Lecz wskutek śmierci w 1278 roku odniesionej w bitwie pod Suchymi Krutami, stracił panowanie nad Austrią, która przeszła pod panowanie Habsburgów na 640 lat.

Początki panowania Habsburgów

Panowanie Habsburgów w Austrii zaczynał zwycięzca spod Suchych Krut Rudolf I Habsburg. Następcą Rudolfa został Albrecht I Habsburg, który próbował przejąć władzę w Czechach i zostać cesarzem. Habsburgowie prowadzili politykę dynastyczną, czego rezultatem było m.in. małżeństwo Elżbiety Rakuszanki z królem polskim Kazimierzem Jagiellończykiem. Prowadzili politykę dążącą do zdobycia tronów dla własnej dynastii, czego skutkiem były traktaty z Wiednia z 1515 roku pomiędzy nimi a Jagiellonami. Wskutek klęski wojsk Ludwika II pod Mohaczem w 1526 roku państwo Habsburgów stało się jednym z najpotężniejszych państw w Europie, ponieważ śmierć króla Węgier spowodowała, że wkrótce ziemie Czech i Węgier dostały się pod panowanie Habsburgów. Jej przedstawiciel cesarz Karol stał się jednym z najpotężniejszych władców, a zarazem głównym obrońcą jedności katolickiej. Wskutek niepowodzeń musiał on abdykować w 1556 roku po pokoju w Augsburgu w 1555 roku. Podzielił on swoje państwo na dwie części pomiędzy syna Filipa II i brata Ferdynanda, który otrzymał Austrię wraz z przyległymi ziemiami. Tym samym nastąpił podział dynastii Habsburskiej na dwie części hiszpańską i austriacką. W 1564 r. cesarz podzielił austriackie ziemie Habsburgów pomiędzy swoich synów. Austrię otrzymał Maksymilian II, późniejszy cesarz, król Węgier i Czech. Styrię, Karyntię i Karniolę odziedziczył arcyksiążę Ferdynand II, a Tyrol i szwabskie posiadłości Habsburgów arcyksiążę Karol. Maksymilian II władca Austrii w swojej polityce działał jako cesarz w Niemczech, prowadził wojnę z Turcją z którą w 1568 roku zawarł rozejm z rządem sułtana Selima II na mocy którego Habsburgowie mieli płacić trybut Turkom. Próbował zdobyć tron elekcyjny dla dynastii w Rzeczypospolitej. W pierwszej wolnej elekcji jego syn Ernest nie został wybrany na króla, natomiast zwyciężył Francuz Henryk Walezy co było klęską dla monarchii Habsburskiej, która walczyła o dominację w całej środkowej Europie. Sam Maksymilian uczestniczył w drugiej wolnej elekcji w 1575 roku i został wybrany na króla polski, lecz jego przeciwnicy wybrali Stefana Batorego. Maksymilian nie chciał zatwierdzić pactów conventów i starania o polską koronę zakończyła jego śmierć w 1576 roku. Jego następcą był Rudolf II Habsburg, który rozpoczął III wojnę austriacko-turecką w 1593 roku. Przyczyną rozpoczęcia wojny była odmowa płacenia trybutu Turkom. W 1609 roku wydał List majestatyczny na mocy którego dawał pewne swobody protestantom w Czechach i na Śląsku, lecz nie przestrzegał ich co w konsekwencji doprowadziło do wybuchu wojny trzydziestoletniej. Próbował przejąć tron polski prowadząc pertraktacje z Zygmuntem III Wazą. Wskutek choroby został zastąpiony na tronie poprzez brata Macieja. Kolejny na tronie zasiadł Ferdynand II. W czasie wojny trzydziestoletniej działania wojenne toczyły się w Czechach, wybuchło powstanie na Węgrzech, które zostało stłumione przy pomocy lisowczyków wysłanych na pomoc przez króla polskiego w 1620 roku.

Bitwa pod Wiedniem

Tureckie zagrożenie dla Europy Środkowo-Wschodniej nie słabło, w 1683 roku Turcy pod wodzą wezyra Kara Mustafy zagroziły swoimi wojskami bezpośrednio stolicy Austrii. Władca Austrii Leopold poprosił polskiego króla Jana Sobieskiego o pomoc wojskową. Na mocy zawartego traktatu pomiędzy Polską a Austrią Jan Sobieski przybył Austriakom z pomocą.

Po pokonaniu Turków 12 września 1683 pod Wiedniem, wojska pod wodzą Sobieskiego zadały ostateczny cios najeźdźcom ze wschodu w bitwie pod Parkanami w październiku tego samego roku. Zwycięstwa polskiego monarchy zahamowały dalszą ekspansję turecką. Następnego roku, Austria zawiązała z własnej inicjatywy Świętą Ligę, która doprowadziła do kresu ambicji tureckich w Europie, co zostało potwierdzone w 1699 roku pokojem zawartym w Karłowicach. W wyniku postanowień karłowickich do monarchii Habsburskiej wróciły Węgry i Siedmiogród.

Austria w XVIII wieku
Karol VI Habsburg wydał w 1713 roku sankcję pragmatyczną, która potwierdza nierozdzielność monarchii Habsburskiej. Karol VI ostatecznie podporządkował w 1718 roku całe Węgry próbujące się wyłamać z monarchii. Prowadził zwycięską wojnę z Turcją. Po jego śmierci tron objęła jego córka Maria Teresa, która w wyniku wojny z Prusami straciła Śląsk, co ostatecznie zostało potwierdzone po wojnie siedmioletniej.

Austria w czasie jej panowania zdobyła nabytki terytorialne kosztem Polski. W 1769 roku zajęła miasta spiskie wkraczając bezkarnie na terytorium Polski. Uczestniczyła w 1772 roku w I rozbiorze w którym zabierała Polsce Ruś Czerwoną i Małopolskę, co uzasadniła prawami dynastycznymi korony węgierskiej do tych ziem.

W 1775 roku do monarchii została przyłączona Bukowina. Maria Teresa wprowadziła reformy wewnętrzne ustanawiając urzędy centralne, tworząc Generalny Komisariat Wojenny oraz reformując oświatę.

Następny władca Józef II Habsburg wprowadził kolejne reformy w duchu oświeceniowym, ograniczające wpływy szlachty i Kościoła na władzę państwową. Innymi reformami były reforma edukacji, armii i sądownictwa. Józef II umocnił austriacką monarchię absolutną, choć pod koniec życia, pod wpływem wydarzeń Rewolucji we Francji z części najbardziej śmiałych reform się wycofał. Austria uczestniczyła w III rozbiorze Polski w 1795 roku, prowadząc politykę wyzysku wobec nowych prowincji polskich. Następcy Józefa II uczestniczyli w koalicjach antyfrancuskich, prowadząc wojny z rewolucyjną Francją w latach 1792–1815 (z przerwami).

Austria w XIX wieku
W wyniku wojen z rewolucyjną Francją Austria stopniowo traciła kolejne terytoria: Niderlandy Austriackie (1795), Lombardię (1796), Tyrol i Wenecję (1805), Prowincje Iliryjskie i ziemie III oraz częściowo I rozbioru Polski (1809). Po proklamowaniu Cesarstwa Francuskiego przez Napoleona, Franciszek II Habsburg ogłosił się cesarzem Austrii (1804). Dwa lata później Napoleon rozwiązał Święte Cesarstwo Rzymskie, którego głową dotychczas byli Habsburgowie. Porażka austriackich wojsk w bitwie pod Austerlitz 2 grudnia 1805 roku przypieczętowała przewagę Napoleona nad Austrią.

Najbardziej dotkliwą klęską Austrii w walce z Napoleonem była wojna roku 1809. Na mocy pokoju z Schönbrunn Cesarstwo Austriackie straciło ziemie na rzecz Francji, Bawarii i Księstwa Warszawskiego.

Po upadku Napoleona w Wiedniu odbył się w 1815 roku kongres, który zdecydował o kształcie mapy Europy.

W wyniku jego postanowień w miejsce dawnej I Rzeszy utworzono jedynie luźny Związek Niemiecki, na czele którego stanęła Austria. Austria zrezygnowała wówczas z ziem utraconych w Niderlandach i Polsce (odzyskała jedynie Wieliczkę i Tarnopol), w zamian za co umocniła swoją pozycję w północnych Włoszech. Habsburgowie dołączyli również do Świętego Przymierza, którego celem było zachowanie status quo w Europie. Wojska austriackie stłumiły powstania wolnościowe we Włoszech oraz kontrolowały inne podległe narody. Kanclerz Klemens Lothar von Metternich sprawował władzę w Austrii do wybuchu Wiosny Ludów. Władze austriackie prowadziły politykę zgodną z absolutyzmem. Austria kładła kres dążeniom niepodległościowym Polaków, próbując poddać ich germanizacji, podpisała układ w Mnichovo Hradiště na mocy którego zobowiązała się do likwidacji samodzielności Krakowa przy pierwszej lepszej sposobności. W 1846 roku Austriacy przyczynili się do wybuchu rzezi galicyjskiej, a następnie w
wyniku powstania krakowskiego zlikwidowali Rzeczpospolitą Krakowską.

W wyniku wybuchu Wiosny Ludów w Cesarstwie wybuchły demonstracje, wystąpienia mające na celu dopuszczenie do władzy ludu. W Austrii wybuchło powstanie węgierskie stłumione przez wojska Iwana Paskiewicza. Demonstracje miały miejsce w Wiedniu, na ziemiach polskich oraz w Czechach. W trakcie Wiosny Ludów na tron wstąpił Franciszek Józef. Austria w wyniku klęski w wojnie z Francją, zawarła porozumienie w którym Cesarstwo zrzekło się pretensji do Lombardii, zatrzymując jednak Wenecję.

Wojska austriackie walczyły z Danią w drugiej wojnie o Szlezwik w 1864. Po zwycięstwie przez Związek Niemiecki (Królestwo Prus i Cesarstwo Austrii), armia austriacka została zaatakowana przez Bismarcka, a następnie pokonana przez armię pruską pod wodzą Helmutha von Moltke pod Sadową w 1866 roku.

Klęski odnoszone w wojnach przyczyniły się do przekształcania Austrii w monarchie dualistyczną, która utraciła swoje wpływy w Niemczech gdzie przewagę zdobyły Prusy po zwycięstwie nad Austrią. Prusy miały wolną rękę w zjednoczeniu Niemiec, które zjednoczyły się po wojnie z Francją w 1871 roku.

Po proklamowaniu monarchii Austro-Węgierskiej w 1867 roku, kraj Habsburski zwrócił uwagę na Bałkany, gdzie rozszerzał swoją strefę wpływów. Wówczas na Bałkanach swoje interesy miała także Rosja, która w XIX wieku dążyła do opanowania Konstantynopola. Już w pierwszej połowie XIX Rosja potwierdziła swoje wpływy na południu Europy, pomagając Grekom w uzyskaniu niepodległości i zwyciężając Turków pod Navarino w 1827 roku, co Klemens von Metternich uznał za polityczną klęskę interesów Austrii. W wojnie krymskiej zaostrzyły się stosunki austriacko-rosyjskie, co nie przeszkodziło w uzyskaniu przez Austrię nabytków terytorialnych w postaci Bośni i Hercegowiny (okupacji) w 1878 roku w wyniku wojny rosyjsko-tureckiej. W 1908 roku Bośnia i Hercegowina została włączona do Austro-Węgier. W trakcie I wojny światowej Austro-Węgry biorą udział po stronie państw centralnych przeciwko Rosji.

Mimo podjęcia w I wojnie światowej sprawy polskiej w postaci planów utworzenia monarchii trójczłonowej składającej się z Austrii, Węgier i Polski, monarchia Austro-Węgier rozpadła się, a ostatni cesarz Karol 11 listopada 1918 zrezygnował z udziału w rządach.

Austria po I wojnie światowej
W wyniku postanowień Traktatu z Wersalu, Austria stała się państwem nieliczącym się na arenie europejskiej.

W 1918 roku powstał plan Karla Rennera i Otto Bauera ("Zagadnienie narodowości a socjaldemokracja") utworzenia w ramach Cesarstwa Austro-Węgierskiego federacji narodów (zakończył się fiaskiem). Planowi zbudowania 15 kantonów narodowościowych przewodził Aurel Popovici. Na propozycję nie przystali głównie Węgrzy, którzy straciliby w wyniku reformy kluczową pozycję w związku z Austrią. Wówczas nastąpiło stopniowe odłączanie się krajów wchodzących w skład Austro-Węgier. Powstały nowe kraje: Czechosłowacja, Polska i Królestwo SHS. Natomiast większość niemieckojęzycznych terytoriów cesarstwa uformowała republikę z socjaldemokratą Karlem Rennerem na czele.

Austria podpisała traktat z Saint-Germain-en-Laye, w którym zgodziła się ze stratami terytorialnymi, ograniczeniem liczby wojska oraz z zakazem połączenia się z Niemcami. Kolejno nastąpiły plebiscyty w Karyntii i w Burgenlandzie wygrane przez Austrię. Oba kraje związkowe w większości zostały przyłączone do Austrii (Karyntia powróciła, natomiast Burgenland był wcześniej terytorium węgierskim, na którym przeważała ludność niemieckojęzyczna).

Przez cały okres międzywojenny w Austrii narastały tendencje do połączenia się z Niemcami, co w konsekwencji doprowadziło do Anschlussu Austrii przez III Rzeszę Adolfa Hitlera 12 marca 1938 roku. Austria weszła w skład tzw. Wielkich Niemiec. Jesienią 1938 do Austrii przyłączona została południowa część zamieszkanego przez Niemców pogranicza odebranego Czechosłowacji (→ Kraj Sudetów) W czasie II wojny światowej w Austrii istniał obóz koncentracyjny Mauthausen-Gusen.

Austria w wyniku klęski Niemiec została zajęta w kwietniu 1945 roku przez wojska radzieckie. Żołnierze Armii Czerwonej dopuścili się przy tej okazji szeregu rabunków i gwałtów. Szacuje się, że około 100 tys. austriackich kobiet i dziewcząt ucierpiało z rąk żołnierzy 2. i 3. Frontu Ukraińskiego. Terytorium austriackie zostało podzielone na cztery strefy okupacyjne.

Austria po II wojnie światowej

Pierwszym prezydentem powojennej Austrii został Karl Renner, kraj uczestniczył w planie Marshalla, co spowodowało wycofanie się komunistów z rządu Leopolda Figla. 15 maja 1955 został podpisany Traktat państwowy w sprawie odbudowy niezawisłej demokratycznej Austrii przez ministrów spraw zagranicznych ZSRR, Wielkiej Brytanii, USA, Francji i Austrii. To w konsekwencji spowodowało neutralność Austrii. Armia Radziecka wycofała się z terytorium kraju. 15 grudnia 1955 roku Austria została przyjęta do ONZ i w 1960 roku do EFTY. W 1961 roku w Wiedniu odbyła się konferencja międzynarodowa z udziałem Johna F. Kennedy'ego i Nikity Chruszczowa. W 1968 roku wyrażono zgodę na powrót do kraju Ottona Habsburga.

W 1973 roku podczas konfliktu żydowsko-arabskiego, Austria poparła Arabów co spowodowało pogorszenie się stosunków z Izraelem, który był popierany przez kraje Europy Zachodniej. W 1986 roku prezydentem Austrii zostaje Kurt Waldheim, były sekretarz ONZ. W 1995 roku Austria weszła do Unii Europejskiej.

W 2000 roku kanclerzem został Wolfgang Schüssel (ÖVP – Partia Ludowa), który przerwał prym rządzenia socjaldemokratycznych (SPÖ) kanclerzy od 1970 roku (Bruno Kreisky, Fred Sinowatz, Franz Vranitzky oraz Viktor Klima). Za koalicji ludowców (ÖVP), którzy zdobyli 26,9% głosów w wyborach parlamentarne w 1999, z FPÖ (Wolnościowej Partii Austrii), którzy także zdobyli 26,9% (różnica 415 głosów), rozpoczął się prawie roczny bojkot Austrii na forum Unii Europejskiej zakończony po opublikowaniu raportu "trzech mędrców".

Austria w XXI wieku

Koalicja ÖVP-FPÖ
1 stycznia 2002 Austria przystąpiła do unii monetarnej wewnątrz Unii Europejskiej, zmiana szyling austriackiego na euro. W 2002 roku nastąpił kryzys rządowy w Austrii w związku z odroczeniem reformy podatkowej. Na zjeździe FPÖ za sprawą krytyki Jorga Haidera ministrów FPÖ w rządzie, doszło do odejścia FPÖ z koalicji. Ponowne przedterminowe wybory z 24 listopada 2002 roku do Rady Narodowej wygrali chadecy (ÖVP) z 42,3 procentowym poparciem społeczeństwa. Natomiast klęskę odniosło FPÖ (10%). Drugie miejsce zajęła socjaldemokracja (36,5%). Mimo takiego rozwoju wyborów odnowiono starą koalicję. W wyniku kolejnych lat rządzenia koalicji w Austrii zanotowano ożywienie gospodarki, spadek bezrobocia do tego poziomu, że w Austrii zatrudniano więcej Niemców, niż Austriaków w Niemczech. Słaba pozycja FPÖ w koalicji doprowadziła do rozłamu w szeregach Austriackiej Partii Wolnościowej. Grupa Haidera 4 kwietnia 2005 założyła nową partię – Sojusz na rzecz Przyszłości Austrii (BZÖ). Mimo odejścia kilku kolejnych ministrów Wolfganga Schüssela, kanclerz z powodzeniem pokierował pracami Unii Europejskiej, podczas przewodnictwa Austrii w pierwszej połowie 2006 roku.

Koalicja SPÖ-ÖVP
1 października 2006 roku miały miejsce wybory parlamentarne, które wygrali socjaldemokraci (SPÖ) (35,3%), nieznacznie wyprzedzając chadeków (ÖVP) (34,2%). Partia Haidera BZÖ zanotowała 4,1%. Po ustąpieniu w styczniu 2007 Schüssela, nowym kanclerzem został Alfred Gusenbauer reprezentujący SPÖ, która do koalicji zaprosiła chadeków. 16 czerwca 2008 z powodu spadku notowań SPÖ, Werner Faymann zastąpił Alfreda Gusenbauera na stanowisku przewodniczącego socjaldemokratów. 7 lipca 2008, Wilhelm Molterer ogłosił wyjście Austriackiej Partii Ludowej (ÖVP) z "wielkiej koalicji". Głównym powodem była rozbieżność w sprawie stosunku do ratyfikacji Traktatu Lizbońskiego. SPO domagała się ponownej ratyfikacji traktatu w referendum, po wprowadzeniu do niego ewentualnych zmian, po odrzuceniu go w referendum irlandzkim w 12 czerwca 2008. ÖVP wykluczała natomiast organizację powszechnego głosowania. W tej sytuacji 9 lipca 2008 parlament austriacki podjął decyzję o rozpisaniu wcześniejszych wyborów parlamentarnych na dzień 28 września 2008. Kanclerz Gusenbauer 7 lipca 2008 zapowiedział, że nie będzie ubiegał się jednak o reelekcję na stanowisku kanclerza i wysunął na ten urząd kandydaturę Wernera Faymanna.

Po zwycięstwie SPÖ (29,43%) w wyborów parlamentarnych i ponownym zawiązaniu "wielkiej koalicji" przez SPÖ i ÖVP (25,99%), Werner Faymann 2 grudnia 2008 zastąpił Gusenbauera na stanowisku kanclerza. Wybory do Parlamentu Europejskiego z 7 czerwca 2009 potwierdziły dominacje partii koalicyjnych na scenie politycznej. W wyborach prezydenckich z 25 kwietnia 2010 reelekcję zapewnił sobie na kolejne sześć lat Heinz Fischer z SPÖ.

Kolejne wybory parlamentarne odbyły się 29 września 2013 i zakończyły się ponownym zwycięstwem ugrupowań rządzących, tworzących "wielką koalicję" – socjaldemokratów (SPÖ) i ludowców (ÖVP). Oba ugrupowania uzyskały najsłabsze wyniki wyborcze od 1945, niemniej posiadały niekwestionowaną przewagę w parlamencie. W kolejnych wyborach w 2017 roku obie partie "wielkiej koalicji" ponownie zdobyły najwięcej głosów. Wybory zakończyły się zwycięstwem ludowców (ÖVP), którzy utworzyli rząd z Wolnościową Partią Austrii| (FPÖ).

Przypisy

Bibliografia
 Artur Patek, Jan Rydel, Janusz Józef Węc: Najnowsza historia świata tom 4 1995-2007, 2008, .

Austria

redpajama_set_name: RedPajamaWikipedia


You bet on a horse to Win or be Placed. However the term "Placed" can vary depending on the type of race and the number of runners: The place portion of this bet pays out at 1/4 of the win odds. A £1 unit stake Each Way bet would cost £2 (£1 to win + £1 to place). For example, if the horse wins at odds of 8/1 the £1 win portion of the stake is multiplied by 8 and returned with the original £1 win betting stake paying out £9, just like a normal 'Single'. And the £1 place portion of the betting stake is multiplied by 1/4 of the odds, so 8/1 becomes 2/1, with the original £1 place betting stake paying out £3 – thus total winnings of £12. But If your horse finishes in second, third or fourth the £1 win portion of the stake is lost and ONLY the £1 place part of the betting stake is multiplied by 1/4 of the odds, resulting in total winnings of £3.
Also called a 'Roll-Up' or 'Acca'. One bet requiring any number of selections but all the selections must win to have a return. The winnings are calculated by placing all the money on the first selection, then the winnings from that bet is placed on the next bet, etc.
A Lucky 15 consists of 15 bets involving 4 selections in different events. The bet includes 4 singles, 6 doubles, 4 trebles, and 1 four-fold. If only one selection wins, as a consolation returns are paid to treble the odds. If all four selections win, a bonus of 20% is added to total returns. For the bonus to apply, all selections must win (does not apply to void or non-runners). If only one of the selections wins, you receive treble the odds. For each-way bets the consolation is paid only on the win part of the bet. Lucky 15 bets are accepted on horse racing, greyhounds only and correct scores.
A Canadian (also known as a Super Yankee) consists of 26 bets involving 5 selections in different events. The bet includes 10 doubles, 10 trebles, 5 four-folds plus an accumulator. A minimum of 2 of your selections must be successful to get a return.
A Lucky 31 consists of 31 bets involving 5 selections in different events. The bets include 5 singles, 10 doubles, 10 trebles, 5 four-folds and a five-fold accumulator. If only one selection wins, returns are paid to four times the odds. If four of the selections win, a bonus of 15% is added to total returns. If all five selections win, a bonus of 25% is added to total returns. For the bonus to apply, all selections must win (does not apply to void or non-runners). For each-way bets the consolation is paid only on the win part of the bet. Lucky 31 bets are accepted on horse racing, greyhounds only and correct scores.
A Lucky 63 consists of 63 bets involving 6 selections in different events. The bet includes 6 singles, 15 doubles, 20 trebles, 15 four-folds, 6 five-folds and a six-fold accumulator. If only one selection wins, returns are paid to five times the odds. If five of the selections win, a bonus of 20% is added to total returns. If all six selections win, a bonus of 33% is added to total returns. For the bonus to apply, all selections must win (none void or non-runners). For each-way bets the consolation is paid only on the win part of the bet. Lucky 63 bets are accepted on horse racing, greyhounds and correct scores.
A Straight Forecast involves 2 selections in 1 race finishing 1st and 2nd in the order named.
A Reversed Forecast involves 2 selections in 1 race finishing 1st and 2nd in either order. As such it is two straight forecasts, AB and BA.
Combination Forecasts involve 3 or more selections in a race, with any 2 to finish 1st and 2nd in any order.
Straight Tricasts involve 3 selections in a race finishing 1st, 2nd and 3rd in the order named.
Combination Tricasts involve 3 or more selections in a race finishing 1st, 2nd and 3rd in any order.


My hope is to use this space to highlight some moments I get to experience on this journey of life! It's an honor to share them with you! Hope you enjoy!
Leave a comment so I know you were here!
ALASKA :: WHALES, ICE & WOW.
Guys, this crew called ME the GOAT, but the real GOAT here is the @uclatheden flying to Fort Worth to cheer on the @uclagymnastics team!
Crossed another state off of my list with an incredible trip to ALASKA!
Wait, is it a little bit Russian?
So you're telling me the sun NEVER goes away?
Will I get to see Shamu in real life?
Are the Northern Lights visible every night? ...because if I see them, ill poop my pants.
You know the usual questions. I'm sure you can relate.
Well, let me tell you - Alaska surpasses all of my expectations and I DID get to see Shamu in real life... 3 of them! ...eating a porpoise like it was a dog toy!
I was invited to Anchorage, Alaska by Samantha Peszek for the first Beamqueen Bootcamp of the year. There was no way I was going to say no to this (although I did have Taylor Swift tickets for the same weekend). The plan was to go up to Alaska a day early, so that we could all do some fun sight seeing in Anchorage. We booked a 5 hour boat tour, Major Marine Tours (LINK HERE &&&&), out of Whittier, Alaska. The pamphlet states that there was a 40% chance of seeing whales, and that was plenty enough for me to be super pumped for it.
The drive to the harbor was gorgeous. About an hour outside of Anchorage, the snow topped mountains, beautiful fjords, wooded hillsides - i was just in awe the whole time. It was definitely chilly while we were there. About mid to low 40s. For this California kid, that was frozen, but just think warm thoughts right?!
I won't bore you with all of the emotions of the day, but let me tell you, that 40% prediction of seeing whales was so off. 3 orcas, 2 humpbacks, a dead porpoise, a bald eagle, beautiful glaciers and a permanent stunning landscape was worth every minute of this trip. According to the captain of our boat, our luck of seeing all of this wildlife and action while on board was very shocking to them. In fact, there was a moment that we were able to witness that the National Parks Ranger on board said in her 20 years of being a ranger, she had NEVER seen. Let me fill you in.
The boat starts to slow down, the captain comes on the intercom, "Just received word that there are a few whales around here." The doors to the deck swung open and I sprinted outside. Gave it about 15 seconds, sure enough, Shamu's little fit was like 150 yards away. Then another fin. Then another one. 3 WHALES! ... but then, as I'm freaking out, there was a lot of splashing that started happening. The volume of collective "wow's" on the boat was rising steadily. THEN... a moment of calm, then a good size Dall's porpoise FLIES through the air, and all the splashing water appears BLOOD RED! If I wasn't freaking out enough before, now I was witnessing the circle of life in action! The Park Ranger and the captain were on the intercom in utter shock of what they were seeing as well. They had never witnessed orca's actively feeding in the wild. I like to think its because I was on board, Shamu x3 decided to put on a show.
phew. that was exhilarating to write in words. I am a little short of breath after reliving that moment again.
Overall, while the boat tour was an INCREDIBLE highlight of our trip and arguably the best way to get to see SO many Alaska things, the rest of our time in Alaska was really cool! It is true, the sun barely goes down. In fact, it didn't set till about 11:30pm every night and rose about 5am. CRAZY! Bring an eye mask to sleep! Everyday driving around town, you could look up and see those beautiful snow-covered mountains, and it never once got old.
Highly reccommend a trip to Alaska in your lifetime. You won't regret it. And actually.. you are welcome to join me when I go next time. YUP, next time! Next trip will be for a Northern Lights viewing trip. Who is with me!?
One of the most frequently made statements that I get from care-givers when I arrive to a hospital visit is, "We have a lot of patients on droplet precautions right now, so we can just stand at their door." I quickly follow-up with, "If you'll allow us, we are more than willing to put on gown, gloves and mask, so we can get as close as we can to the kids!"
Now, to some this may sound pushy, but the reality is, the hospital sees a lot of visitors that are not interested in going for those genuine moments of sitting bedside for fear of the unknown, but the truth is, droplet precautions are not for my protection, it is for the protection of the patient. This means, if the care-giver will allow us to put on the necessary garments to ensure our presence doesn't harm the patient, we are ALL IN.
When I was in New York last month, I posted the photo below. What struck me most, was the amount of responses that I received from courageous families fighting cancer, appreciating my voice and mindset about this topic.
"THANK YOU FOR SAYING THOSE WORDS. I actually wouldn't get visitors when I was in a lot of heavy chemo treatment because they were required to wear all of that!"
These words were so crazy to hear. I knew it was true that this was something that kids were feeling when visitors would just stand at the door, or not visit at all, but those words show how important it is for these kids to feel supported and encouraged to NEGU by the people around them. These kids are often in the hospital for days, weeks and some even months or years at a time. It is such a privilege for me to have the opportunity to be a smile in their time at the hospital, but I know the reality is, most of their time at the hospital isn't as joyful. It's a lot of fighting, tests, pills, treatments, bad news, surprising news, etc. It's a breath of fresh air for them when they get a visitor, whether its a friendly stranger with a gold medal, or a familiar face in their friends and family; I believe it is so healing for them to feel things that have nothing to do with their disease.
I can assure you, with Team NEGU, we will always do whatever it takes to get as close as we can to the kiddos without putting them at risk! These kids need a moment of escape, a moment to feel normal. They need people like us to visit them. And that will not stop.
I am so honored to be a vessel of encouragement to kids in their fight with cancer.
As we quickly approach summer, I am getting quickly pumped for the beach days, pool hangs and warm summer nights. To expedite all of those feelings, I jumped in front of Sierra Ashely Co's camera and snapped a few fun shots at the Pacific City Shopping area in Huntington Beach. I loved rocking these new pieces from Urban Outfitters and Forever 21.
I thoroughly loved shooting with Sierra! She is high energy, positive, encouraging and innovative to work with. She genuinely loves to CREATE. Her passion for healthy living, creating memories and relationship is contagious. Shooting together was truly collaborative as we meandered through the shopping area looking for rad walls, cool plants and interesting corners to shoot. Not gonna lie though, there was a lot more talk about life and current updates than talk about the shoot, what angles to capture or any other specifics. Those are the best kind of shoots right?! You can check out her instagram (here)! Go give her some love!
On the Warner Brothers Studio Lot in Burbank, CA, there is an incredible behind the scenes experience open to the public. The Warner Brothers Studio Tour Hollywood showcases the best of the best in preserved film sets, up close views at Hollywood movies and tv show props and costumes and the best of the best tour guides informing attendees of the coolest fun facts all along the way.
I was invited to be apart of the press opening of the Fantastics Beasts and Where to Find Them & Harry Potter exhibit this year. It was super cool to see props up close such as Harry Potters glasses and wand, original costumes from the Fantastic Beasts movie and even a sorting hat experience where I was able to officially get sorted into my Hogwarts House. Guys, I am officially a Hufflepuff. How exciting?!
I sported an official Newt Scamander coat and it was the talk of the event. People loved it! Some people even said I looked JUST like the character!
Thank you Sparkloft Media Group for having me at this event. It was such a rad event! If anyone is interested in taking the Studio Tour, you can head to the link (here) to set up your tour! I HIGHLY recommend it!
Modeled after the infamous ride-alongs with James Corden for his evening talk show - I was asked to host some of the UCLA Gymnastics Team members in Carpool Choreography! In the spirit of my heart for this blog space, I must tell you about the brilliancy of the Videographer, Editor, Director, Co-Producer & Sound Mixer for Carpool Choreography, Deanna Hong!
Deanna is one of the most brilliant story tellers I have ever worked with in my time in the industry. She has a natural niche for pulling out the beautiful and most acclaimed parts of a person's story. She knows the right questions to ask, the best angles to shoot at and is always there to capture those unforgettable moments. I can definitely relate to Deanna because we both did not grow up around the sport of Gymnastics. Since entering into the world of this sport, we have both absorbed as much knowledge about the sport so that we can do our best with our jobs accordingly. This has been the biggest challenge, but greatest gift for the both of us as we both have become well known in our own respective niche. Deanna's passion for this sport even lead her to working for NBC this summer during the Rio Olympic Games! Talk about hard work and dedication paying off!
You all need to go and check out her other work on her Instagram (click here) or Youtube (click here) to see her story telling brilliancy! It was amazing working with her on the Carpool Choreography Series, and can't wait to work on more projects in the future!
First meeting Krizia Loechle was through Instagram DM. Thats becoming the place where all the business deals are going down! She was very pleasant to communicate with and was really excited to create some images together. The best part of it all, she was local in Orange County!
We got the shoot scheduled and she took down all of my sizes and we were ready to go! When I showed up to our meeting place, Krizia busted out three different outfits to shoot that day and was excited to shoot them up at the Top of the World location in Laguna Beach. If there was one thing I noticed about Krizia from the start, it was her joy for photography and creating. That joy was contagious throughout our time together and I think it definitely came across in the final product!
One of my favorite looks, whether it is interior design or just vibes in general is the "wood vibe". To me its cozy, warm, organic and upscale. I have recently had the best time filling my new apartment space with black and wood trends - it makes me so stoked. Wood shelves, wood floors, wooden decor - you name it, it fits the trends and vibes I am going for. Actually, about 3 years ago, when my wood obsession really became a thing, I asked for a couple different wood accessories for Christmas, but clearly my family and friends didn't understand just how fascinated I was by this new trend.
About two weeks ago, I put a new watch on my wrist that was made of wood and it was then that my family and friends realized that I wasn't crazy - this trend was actually really sweet.
It is only fitting that my very first brand deal as an influencer was for an incredible Wood Watch company called JORD Wood Watches (click here to website). When I got their e-mail, I was so pumped because I have never found a wood watch that I fell in love with, but looking at their line, there wasn't a single watch I didn't like. Check out my new time piece from JORD below and head over to their website and sign up for a contest that is going on right now during this season of deals between Black Friday and Cyber Monday! These watches definitely would make a great gift this holiday season.
Here's the contest - It's a giveaway! It's a $75 e-voucher for the winner, and everyone who enters gets a $20.00 e-gift card excluding the winner. CLICK HERE to enter!


Linde LLC will invest over $100m to increase the merchant liquid and gaseous product production capabilities of its industrial gases plant in Delaware, US.
Once the expansion project is complete, the facility will become the Tier One player's largest liquid merchant plant in the country.
Linde Engineering will install a new air separation unit (ASU) at the Claymont site which will produce 1,200 tonnes per day (tpd) of liquid oxygen (O2), nitrogen (N2) and argon (Ar), as well as 400 tpd of gaseous products.
The plant is due to be commissioned in 2019 and will serve customers across the Delaware Valley via pipeline.
The gases business in the Mid-Atlantic region of the US achieved revenues of approximately $2.1bn in 2015, with the merchant market accounting for the vast majority of this total. Linde currently holds a territorial market share of around 17%, operating a strong network of both onsite and merchant plants throughout.
The Linde Group has issued two significant executive level departures in the last hour, including the immediate exit of Chief Financial Officer Georg Denoke and the impending end of Dr. Wolfgang Büchele's role as CEO of Linde AG.
The Linde Group has announced plans to build a new, large-scale air separation unit (ASU) in the US, representing a total investment of $40m.


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TTNP
BBD.B:CA
/CL:NMX
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/GC:CMX
/SI:CMX
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Matson Inc. (MATX) Plunges 7.46% on October 24
Equities Staff Follow	| Wednesday, 24 October 2018 17:11 (EST)
Matson Inc. (MATX) had a rough trading day for Wednesday October 24 as shares tumbled 7.46%, or a loss of $-2.65 per share, to close at $32.89. After opening the day at $35.64, shares of Matson Inc. traded as high as $35.79 and as low as $32.79. Volume was 266,521 shares over 2,765 trades, against an average daily volume of 211,399 shares and a total float of 42.7 million.
As a result of the decline, Matson Inc. now has a market cap of $1.4 billion.
The stock has a P/E Ratio of 6.2.
In the last year, shares of Matson Inc. have traded between a range of $40.60 and $26.55, and its 50-day SMA is currently $37.58 and 200-day SMA is $34.04.
For a complete fundamental analysis of Matson Inc., check out Equities.com's Stock Valuation Analysis report for MATX.
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Matson Inc is a holding company, consisting of two segments, ocean transportation and logistics. The company also provides container stevedoring, container equipment maintenance and other terminal services for MatNav and other ocean carriers.
Matson Inc. is based out of Honolulu, HI and has some 1,947 employees. Its CEO is Matthew J. Cox.
Matson Inc. is a component of the Russell 2000. The Russell 2000 is one of the leading indices tracking small-cap companies in the United States. It's maintained by Russell Investments, an industry leader in creating and maintaining indices, and consists of the smallest 2000 stocks from the broader Russell 3000 index.
Russell's indices differ from traditional indices like the Dow Jones Industrial Average (DJIA) or S&P 500, whose members are selected by committee, because they base membership entirely on an objective, rules based methodology. The 3,000 largest companies by market cap make up the Russell 3000, with the 2,000 smaller companies making up the Russell 2000. It's a simple approach that gives a broad, unbiased look at the small-cap market as a whole.
To get more information on Matson Inc. and to follow the company's latest updates, you can visit the company's profile page here: MATX's Profile. For more news on the financial markets and emerging growth companies, be sure to visit Equities.com's Newsdesk. Also, don't forget to sign-up for our daily email newsletter to ensure you don't miss out on any of our best stories.
All data provided by QuoteMedia and was accurate as of 4:30PM ET.
DISCLOSURE: The views and opinions expressed in this article are those of the authors, and do not represent the views of equities.com. Readers should not consider statements made by the author as formal recommendations and should consult their financial advisor before making any investment decisions. To read our full disclosure, please go to: http://www.equities.com/disclaimer
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redpajama_set_name: RedPajamaCommonCrawl


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Special BFG Announcements
Roots Blues Airplay Charts (click chart for links to sample tracks)
Get Your Magazine ~ Tweet ~ Post Fests
Order your 14th Annual Blues Festival Guide
Get your copy of 2016 Blues Festival Guide magazine and enjoy our various feature stories and of course, find hundreds of festivals and also blues related ads. Pick up a copy at a blues festival, via your local blues society or order one to have shipped directly to you!
Want to hold in your hands now! Click here to order!
You can also NOW find the DIGITAL magazine online!
Hey, come on over and Join over 10,000 Blues Freaks at
our Twitter feed! @BluesFestGuide
Promoters! Post Your 2016 Festival Dates
Festival promoters! Post their 2016 festival dates on our top-ranking
blues festival website. You don't need your line-up, just dates and venue. Free & easy!
Show off your 2016 BFG Magazine!
We caught up with Frank Roszak of Frank Roszak Promotions in Memphis during the 2016 BMA event weekend. Roszak received the Keeping The Blues Alive Award for Publicist in 2014.
Photo: Cheryl O'Grady-Yearnshaw
*NOTE! The 14th annual edition can be found via blues societies and festivals, etc. When you get yours, snap photos of you, your friends, artists, etc. with the 2016 Guide! *EMAIL us your photo plus caption & credit.
*Want your own hard copy? Order via our website now!
Our 2016 edition is sponsored by the Big Blues Bender.
Lew Jetton & 61 South :: RAIN
Rain, the new CD from Lew Jetton & 61 South, promises to further Jetton's reputation as a clever songwriter, and dynamic, original vocalist. The band's previous 2 releases, State Line Blues and Tales From A 2 Lane, were both "Picks to Click" on XM/Sirius Radio's Bluesville Channel, and Rain promises to take up where the other two left off.
The songs on Rain range from poignant ("Lay Me Down") to rousing gospel ("Glory Train") to contemporary "(Who's Texting You") to humorous ("Move On, Yvonne"). Think a little southern-fried Chicago, seasoned with cajun and creole spices.
Rain brings together the longtime 61 South bandmates, along with several of Jetton's buddies, including 2-Time International Thumbpicking Champion and IBC Semi-Finalist Alonzo Pennington, former multi-instrumentalist for guitar legend Johnny Hiland, J. Solon Smith on piano, former Lonnie Mack backup vocalist Miranda Louise, J.D. Wilkes, harp ace... Complete details about this release here on our website
"Who's Texting You"
Various :: BLUES FOR BIG WALTER
EllerSoul had wanted to do a project for some time and that was to get together some great friends and blues harmonica players and pay respect to one of the all-time greats, Big Walter Horton. The result is Blues For Big Walter.
Artists appearing include Kim Wilson with Big Jon Atkinson, Mark Wenner, Mark Hummel, Steve Guyger, Sugar Ray Norica, Anthony Geraci, Bob Corritore on tracks with Jimmy Rodgers and Robert Lockwood, Kurt Crandall, and Li'l Ronnie Owens, plus Henry Gray, Chico Chism, Sue Foley, Mike Welch, Steve Willis, Bob Welsh, Bill Stuve and more.
Blues For Big Walter is a non-profit project with proceeds going to The Blues Foundation's HART Fund. Everyone involved donated music for the cause.
EllerSoul hopes they get to do a Volume II because they're so many great players they just couldn't get on this one CD.
"My Babe"
24th Annual Chenango Blues Fest Aug 19-20
(Norwich, NY) - The 24th Annual Chenango Blues Fest on August 19th and 20th promises to be one for the books with artists from Woodstock headliners Canned Heat to Jam/Blues Rocker Anders Osborne, to soul bluesman Curtis Salgado, to the swingin' roots of Duke Robillard, to soulful, triple threat Carolyn Wonderland and everything in between! The fest features two stages and will be held at the Chenango County Fairgrounds (168 East Main St., Norwich), in beautiful central New York. In addition to award-winning blues acts the festival also features arts and craft vendors, food and beer vendors, children's activities, and camping. Tickets are $25 in advance or $35 day of show. See their website for advanced ticket locations and more information. Friday night show is always free to the public!
...Find full article and artist photos on our website
Joseph Rosen Photo Exhibition in Clarksdale Aug 13-14
(Clarksdale, MS) - Famed photographer Joseph Rosen will be having an exhibition of photographs from his book, Blues Hands at the Delta Blues Museum in Clarksdale, MS. The show is being hung this week, and there will be a preview and a book signing this Saturday, August 13 at 2:30 pm during the annual Sunflower River Blues Festival. The following day, Sunday, August 14th, Joseph will also be signing books at the Cathead Delta Blues & Folk Art Store in Clarksdale during the Cathead Mini-Festival.
There will also be an opening reception on Thursday, September 8th from 5pm to 7pm at the Delta Blues Museum.
If you are in the area, drop by to any or all of these events and say hello, get a signed book, support the Delta Blues Museum, Cathead and Clarksdale.
Here are some links to learn more about the book, the Delta Blues Museum and Cathead. ...Find here on our website
Morristown Jazz and Blues Festival Saturday, Aug 20
(Morristown, NJ) - The sixth year annual, free Morristown Jazz & Blues Festival will come to the Morristown Green on Saturday, Aug. 20, with performances starting at noon and running through 10 pm Saturday. The event with headliner Robert Randolph & The Family Band, will feature blues, soul, swing and more plus celebrating local favorite guitarist Bucky Pizzarelli's 90th birthday and paying tribute to the late bassist Rusty Paul. Parking is available in the public lots and the train station is just a couple of blocks away. Bring blankets and beach chairs.
Performers will include special guest headliner Robert Randolph & the Family Band, the pedal steel guitarist who draws from blues and soul; Quinn Sullivan, young blues guitarist extraordinaire; Louis Prima Jr. and the Witnesses, only son of the incomparable Louis Prima paying tribute,
...Find full article and more artist photos on our website
It's John Lee Hooker Month at Delta Blues Museum plus the 29th Sunflower River Blues & Gospel Fest is here
(Clarksdale, MS) - The Delta Blues Museum in Clarksdale, MS, is excited to honor the important work of native son, John Lee Hooker, and they plan to make it an annual event at the museum.
For John Lee Hooker Month, the Museum has special items on sale in their Gift Shop: CDs and vinyl, DVDs, and his biography, Boogie Man. The book "gives an account of an entire art form. Grounded in a time and place in American culture, the blues are universal, and in the hands of the greatest practitioners its power resides in the miracle of using despair to transcend it." It's "the authoritative biography of the musician whose career spanned over fifty years and included over one-hundred albums and five Grammy Awards. ...Find full article and event photos on our website
Blues On The Hill Aug 20 in Texas
(Harlingen, TX) - Blues on the Hill is an annual concert series that features national and international Blues Music Artists. The event has been a family oriented cultural event in Harlingen for the last 12 years. Their August 20th event will be held at McKelvey Park (1325 S. 77 Sunshine Strip) in Harlingen, Texas and feature Katy Guillen & The Girls with special guests Tim Gonzalez and Soul Pocket, and Evelyn Rubio.
2014 finalists at the International Blues Challenge in Memphis, TN, Katy Guillen & The Girls have deep roots in the blues, thanks to leader Guillen's considerable skills and long history as a blues guitarist, but this trio—Guillen (guitar, vocals), Claire Adams (bass, vocals), and Stephanie Williams (drums)—brings a wide range of talents and tastes to the band's sound.
...Find full article on our website
A mural depicting town's blues music roots considered for historic downtown building
(Aurora, IL) - A mural that commemorates Aurora, Illinois connection to the history of blues music could reside on the side of a downtown building by September.
With final approval, the 14-foot by 30-foot mural, painted as part of an international event that took place in Aurora in 2008, would be installed on the side of the historic Silver Plate Building at 6 E. Downer Place for at least five years.
The mural honors Aurora's past connection with blues music and was painted by a group of artists, under the direction of Patrick Kirwin, of Alexandria, Virginia, as part of the international Salon Forever event that took place at the Painters and Allied Trades Council 30 union hall in Aurora in 2008.
...Find more about the mural on our website
~ LRBC #29 Pre-Book Started today 7/21/16
~ Limited Cabins Remain for the LRBC #27 ... Act now!
~ Join Waitlist for LRBC #28
LRBC #29 Southern Caribbean Oct-21-28, 2017: PREBOOK HAS STARTED Thursday July 21 for LRBC #29 Ft. Lauderdale to Aruba, Curacao, Half Moon Cay, Bahamas
Visit reservations.bluescruise.com or call (816) 753-7979. Your fully-refundable deposit of $500 per cabin holds a space in line to book a cabin when the artist announcement is made (likely in late Nov. '16).
LRBC #27 Southeastern Caribbean, Oct. 29-Nov. 5, 2016
LIMITED CABINS REMAIN!! San Juan, Puerto Rico to the exotic islands of Barbados, Dominica, Grenada & Guadeloupe on the Celebrity Summit.
LRBC #28 Eastern Caribbean, Jan. 22-29, 2017
SOLD OUT. Join Waitlist! Ft. Lauderdale to St. Maarten, St. John USVI & Dominican Republic on Holland Aerica's new ms Koningsdam.
NOTE: If you need help, please email or visit Booking FAQs or call (816) 753-7979 to join. Visit reservations.bluescruise.com
Aug 13-14, 2016 Radio Show: DUOS
This week the Bluesmobile demonstrates how two heads are better than one. A program dedicated to duos. Sam and Dave, Sonny Terry and Brownie McGhee, Moreland and Arbuckle, The Blues Brothers, and many more.
Good things come in two's this week when Elwood plays great blues duos on the Bluesmobile.
EDDIE KIRKLAND ...Live at The Banana Peel
Thoughts & Birthdays
~ Birthdays of note through next week:
Aug 11-Sam Collins (1887); Aug 12-Percy Mayfield (1920), Roy Gaines (1934); Aug 13-Jimmy McCracklin (1921),
Aug 14-Larry Graham (1946), Son Seals (1942);
Aug 16-Eddie Kirkland (1928), Melvin "Lil' Son" Jackson (1915); Aug 17-Luther Allison (1939),
Albert Washington (1935)
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Sunflower River Blues & Gospel Festival 29th Annual
Aug-12-2016 - Aug-14-2016
Clarksdale, Mississippi, USA
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Mystic Blues Festival
North Stonington, Connecticut, USA
Navasota Blues Fest
Navasota, Texas, USA
Heritage Music BluesFest
Wheeling, West Virginia, USA
Waukesha BluesFest
Delafield, Wisconsin, USA
Norwich, New York, USA
Rosarito Beach, Mexico
Trinidaddio Blues Fest
Trinidad, Colorado, USA
European Blues Cruise
Aug-27-2016 - Sep-01-2016, Marseilles, France
please go to our website
4th Nickel Plate District Amphitheater Blues Fest
Sep-02-2016 - Sep-03-201
Fishers , Indiana, USA
Rentiesville Dusk til Dawn
Sep-02-2016 - Sep-04-2016
Rentiesville, Oklahoma, USA
Lehrter Bluesfestival
Lehrte, Germany
Sonoma County Cajun Zydeco & Delta Rhythm Festival
Sebastopol , California, USA
Bowlful of Blues 24th Annual
Newton, Iowa, USA
Big Blues Bender
Russian River Jazz & Blues Festival
Sep-10-2016 - Sep-11-2016, Guerneville, California, USA
San Diego Blues Festival AimLoan.com
Telluride Blues & Brews Festival
Telluride, Colorado, USA
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Apoptosis is widely known as programmed cell death eliciting no inflammatory responses. The intricacy of apoptosis has been a focus of an array of researches, accumulating a wealth of knowledge which led to not only a better understanding of the fundamental process, but also potent therapies of diseases. The classic intrinsic and extrinsic signaling pathways of apoptosis, along with regulatory factors have been well delineated. Drugs and therapeutic measures designed based on current understanding of apoptosis have long been employed. Small-molecule apoptosis inducers have been clinically used for eliminating morbid cells and therefore treating diseases, such as cancer. Biologics with improved apoptotic efficacy and selectivity, such as recombinant proteins and antibodies, are being extensively researched and some have been approved by the FDA. Apoptosis also produces membrane-bound vesicles derived from disassembly of apoptotic cells, now known as apoptotic bodies (ApoBDs). These little sealed sacs containing information as well as substances from dying cells were previously regarded as garbage bags until they were discovered to be capable of delivering useful materials to healthy recipient cells (e.g., autoantigens). In this review, current understandings and knowledge of apoptosis were summarized and discussed with a focus on apoptosis-related therapeutic applications and ApoBDs.
Apoptosis is a highly regulated process of cell death. Unlike necrosis which is a traumatic version of cell death, apoptosis is a rational and active decision made to sacrifice specific cells for the greater benefits of the organism. It is a normal physiologic process routinely carried out in multicellular organisms . While many enigmas still remain in relevant research areas, it has been well-documented today that apoptosis confers advantages to multicellular organisms in a coordinated manner whereby organisms maintain homeostasis and fine-tune life cycle . Its importance, both to multicellular organisms and to researchers, can be inferred from various biological responses and changes pertaining to apoptosis, e.g., embryonic development, cell renewal and turnover, and externally induced cell death (chemicals, radiations, etc.). One widely exploited function of apoptosis in the biomedical field is obliteration of cancer cells in response to extrinsically applied apoptosis-inducing stimuli such as small-molecule drugs. With apoptosis in the research spotlight, the profound therapeutic potential of apoptosis has enabled researchers to develop promising therapeutic solutions focusing on voluntary death of aberrant cells. A spectrum of drugs and therapies exploiting apoptosis has been proven effective against diseases. Funds and research efforts are being extensively invested in apoptosis-based research and clinical trials.
One notable feature of apoptosis is it exerts its effects mainly through action of a type of serine proteases known as caspases. A death signals are relayed through signaling pathways which ultimately lead to activation of caspases responsible for the execution of cell destruction . Both external and internal stimuli, coupled to extrinsic and intrinsic apoptosis pathways, can initiate apoptosis. Despite many dissimilarities in different pathways, they converge to form apoptotic bodies (ApoBDs) which are eventually engulfed by phagocytes in a process known as efferocytosis . Traditional views regard efferocytosis as the end point of apoptosis and therefore it biochemically concludes the life of morbid cells, whereas accumulating evidence converge to implicate on transfer, recycling and even reuse of materials packaged in ApoBDs . A substantial part of current interest in apoptosis-related researches lies in apoptotic body formation. Apoptotic cells can also be effectively phagocytosed as a whole. In this review, current knowledge about apoptosis is discussed with a focus on therapeutic applications and ApoBD.
Many forms of cell death exist, most of which can be triggered by various stimuli and physiological conditions. Among them, apoptosis and necrosis have been a well-known duo frequently being compared. In 1965, John Foxton Ross Kerr at University of Queensland made the first distinction between apoptosis and necrosis. Further refinements aiming to better interpret apoptosis followed. But it was not until 1972 when the term 'apoptosis' was first proposed by Kerr et al. . Apoptosis has attracted much interest due to its intricate nature and diverse roles in maintaining a healthy and self-sustainable biological entity. Necrosis, on the other hand, is a form of cell injury in response to acute external damages and trauma, resulting in passive cell death which elicits inflammatory response . Comparisons between apoptosis and necrosis reflect the unique features of each other and help researchers to elucidate their respective biological significance.
In cell cycle, apoptosis acts as a fail-safe measure that ensures fidelity and quality of proliferation. While certain degrees of genetic variation are allowed and favored for evolution, reproduced cells with extensive genetic errors and cellular damages are subjected to apoptosis. A key player in the cell cycle machinery, p53, initiates apoptosis in certain cell types. p53 is an extensively studied tumor suppressor. Overwhelming evidence points to its exceeding importance in prevention of cancer development. The p53 tumor suppressor gene is most frequently mutated (mutated in over 50% of all human cancers) in cancer cells , rendering the restrictive mechanism ineffective. Tumorigenesis is likely to commence when the p53-based preventive system malfunctions or loses its function completely.
Stimuli such as DNA damage, hypoxia, and expression of certain oncoproteins (e.g., Myc, Ras) activates the p53-dependent apoptotic pathway . Once committed, p53 paves way for apoptosis by activating pro-apoptotic factors (e.g., Bax) while suppressing antiapoptotic factors (e.g., Bcl-2) . As a well-known tumor suppressor, p53 has been recognized for its critical function to initiate apoptosis in cell cycle, along with the ability to induce cell arrest and DNA repair in recoverable cells. There are many other cell cycle regulators besides p53 that can influence apoptosis (e.g., pRb, p21). Nevertheless the mechanistic details of apoptosis in cell cycle are beyond the scope of this review.
Many researches highlighted the importance of apoptosis in the self-defense mechanism, or in other words, the immune system. The immune system is in charge of defensing the host against an array of external pathogens. Apoptosis is an integral part of the immune system where it facilitates to maintain a homeostasis of the immune system. For example, apoptosis is burdened with the responsibility to regulate immune responses, i.e., to induce death of T and B cells at certain time point to limit an immune response because a prolonged response would otherwise be deleterious to self. Second, the immune system depends upon apoptosis to eliminate unneeded T and B cells to be functionally mature . For example, immune cells targeting self-antigens must be killed by apoptosis to prevent an attack on self. Or B cells that fail to generate antibodies of higher affinity for antigens are subjected to apoptosis as well. Lastly, cytotoxicity of certain types of cells (i.e., cytotoxic T lymphocyte and natural killer cells) is conferred by apoptosis. The well-coordinated killing protocol allows these cells to destroy target cells with themselves remaining intact. Cytotoxic T lymphocyte (CTL) can induce death in target cells through two pathways, one of which involves perforin and granzymes. Perforin and granzymes are contained within the granules excytosed from the CTLs in a directed manner. T cell receptors on CTL help to recognize a target cell (e.g., a cell infected by virus) and unload the granules on the surface of the target cell. Perforin, which is a protein capable of forming pores on the surface of cells, is released in a degranulation process and aid the entry of granzyme into the cell by punching holes on the cell surface . Granzyme, which is also a serine protease, is key to DNA degradation associated with apoptosis in the target cells . Distinct from the extrinsic and intrinsic pathways of apoptosis, perforin–granzyme-mediated apoptosis is exclusively employed in cytotoxic killing mediated by T cells.
Apoptosis plays an indispensable and irreplaceable role both under physiological and pathological conditions. Anomalies in apoptosis have become a major field of interest to researchers and are associated with a broad spectrum of pathological conditions, e.g., developmental defects, autoimmune diseases, cancer, etc. Some diseases pertain to deficiency of apoptosis while others pertain to its redundancy. For example, one of the hallmarks of cancer is evasion of apoptosis, meaning insufficient apoptosis overwhelmed by the limitless replicative potential of cells . On the other hand, too much apoptosis is linked to certain pathological conditions such as acquired immune deficiency syndrome (AIDS). AIDS is a type of autoimmune disease caused by human immunodeficiency virus (HIV) infection . HIV infects it host through binding to CD4 receptors on T cells, followed by subsequent internalization into T cells. Once inside the T cells, HIV increases the expression of Fas receptor which in turn incurs excessive apoptosis of T cells .
Certain morphological changes exhibited by apoptotic cells have been well identified and documented. These changes include cell blebbing and shrinkage, nuclear fragmentation, condensation and fragmentation of genetic materials (chromatin and nucleosomal DNA), and formation of small vesicles known as ApoBDs. Cells undergo a characteristic shrinkage during the early stage of apoptosis. Cell size becomes smaller while the contents within the cells experience a denser packing. Another phenomenon known as pyknosis (irreversible condensation of chromatin) also occurs concomitantly at the early stage of apoptosis. These changes can be observed by light microscopy while electron microscopy can better visualize subcellular changes like pyknosis. Following the early stage of apoptosis, another phenomenon known as karyorrhexis, which refers to fragmentation of the nucleus, ensued. Karyorrhexis is accompanied by further blebbing of the plasma membrane that tears apoptotic cells into small ApoBDs. Current knowledge states that ApoBDs contain remnants of apoptotic cells (i.e., cytoplasm, organelles, and nuclear contents) where the contents of apoptotic cells are randomly distributed to each apoptotic body. Therefore, a specific organelle or a nuclear content may be or may not be present in a particular apoptotic body. These ApoBDs are then engulfed by phagocytes, e.g., neutrophils, macrophages, and dendritic cells (DCs), for final degradation. Phagocytosis marks the terminal step of an apoptotic cycle and it is believed that the essence of this step is to prevent spillage of hazardous materials packed within the apoptotic cells into the surroundings. The reason for forming ApoBDs has remained elusive. Details regarding ApoBDs will be discussed in the next section.
The biological mechanism of apoptosis is exceedingly sophisticated. A complete implementation of apoptosis involves interplay of a wide array of proteins and signal transducers as well as cascades of signaling pathways. Two major apoptosis pathways exist: extrinsic and intrinsic. The extrinsic pathway refers to receptor-mediated initiation of apoptosis. The death receptors in the extrinsic pathway are all anchored to the cell membrane by their transmembrane regions. Upon interaction with an extracellular ligand, membrane receptors relay death signals into intracellular space via their cytoplasmic death domains. Membrane receptors involved in apoptosis belong to the tumor necrosis factor (TNF) receptor superfamily, whose activation depends upon two major ligands: TNF and Fas. TNF and its receptors, namely TNFR-1 and TNFR-2, are responsible for initiating a major apoptosis pathway: the TNF pathway. The interaction between TNF and its receptors has been shown to relay death signal through recruitment of two adaptor proteins: TNF receptor-associated death domain (TRADD) and Fas-associated death domain protein (FADD), and effect programmed cell death through the action of caspases. TNF ligands form homotrimers which bind to TNF receptors on the membrane. Upon binding, adaptor proteins are recruited (TRADD, FADD, and RIP) to TNF receptors on the cytoplasmic side where death domains on the adaptor proteins interact with its counterparts on the receptors. FADD recruits its downstream interactor, procaspase-8 in this case, via homotypic interaction of the death effector domains (DED). Procaspase-8 then undergoes auto-cleavage to yield active caspase-8 which initiates the execution phase of cell death. Caspase-8 cleaves procaspase-3 via proteolytic cleavage to produce active caspase-3 responsible for the final execution of proteolytic degradation of a variety of intracellular proteins. Fas-mediated pathway undergoes a much similar signaling process. FasL (Fas ligand) triggers the pathway by binding to Fas receptors (also known as CD95). FADD associates with the Fas receptors and recruits caspase-8. Fas receptors, along with FADD and procaspase-8, form the death-inducing signaling complex (DISC).
A third extrinsic apoptotic pathway has been shown to be therapeutically exploitable, the TNF-related apoptosis inducing ligand (TRAIL) pathway. TRAIL, alternatively known as Apo2L, was first identified by its sequence homology to FasL . It is a type II transmembrane protein containing an extracellular region which, upon proteolytic cleavage by protease, releases a soluble portion that acts as a ligand. Trimeric TRAIL binds to receptors on the membrane, namely DR4 and DR5, which then trigger intracellular signaling cascade similar to the Fas pathway [17,18]. The TRAIL-DR4/DR5 pathway is proposed to function in a wide range of physiological processes such as T cell activation and tumorigenesis. TRAIL is recognized as a tumor suppressor for its ability to exclusively induce apoptosis in malignant cells and xenografts, rendering TRAIL an ideal antitumor agent [16,19]. The TRAIL pathway also functions independently of p53 which is frequently mutated in cancer cells, yet endowing TRAIL with another crucial therapeutic advantage . However, a considerable number of cancers are resistant to TRAIL treatment . Research on TRAIL has led to emergence of different variants of TRAIL possessing enhanced therapeutic efficacy than its precursor. Yao et al. first reported that RGD-TRAIL exhibited enhanced antitumor effect than wild type TRAIL in multiple tumor cell lines . Receptor-specific TRAIL variants (i.e., specific to either DR4 or DR5) have also been shown to be more efficacious . Another research group led by Dr. Hua recently engineered a novel variant of TRAIL constructed by linking Annexin V and TRAIL . This variant, designated as TP8, showed surprisingly higher antitumor potency than RGD-TRAIL towards A549 cells.
The intrinsic pathway of apoptosis is characterized by non-receptor-mediated initiation and mitochondrial regulation. In the intrinsic pathway, stimuli directly generate intracellular signals which lead to biochemical changes within the cell. When a stimulus is present, it elicits disruption of the mitochondrial transmembrane that dissipates the membrane potential, rendering it more permeable. The stimulus also results in formation of mitochondrial permeability transition pore (MPT) on the outermembrane that channels pro-apoptotic factors into the cytosol . Apoptosome cleaves procaspase-9 to yield active caspase-9 which in turn activates the effector caspase (i.e., caspase-3). Another group of proteins known as SMACs (small mitochondria-derived activator of caspases) bind to IAP (inhibitor of apoptosis proteins) following their release into the cytosol . SMACs deactivate IAP, allowing apoptosis to proceed. Other inhibitors of IAP have been reported such as DIABLO and Omi [27,28]. These proteins engage in the caspase-dependent pathway of apoptosis. A second group of proteins known as apoptosis-inducing factors (AIFs) function in the caspase-independent pathway of apoptosis . AIFs are anchored to the inner membrane of the mitochondria. Upon cleavage by calpain, which is a calcium-dependent protease, AIFs can translocate to the nucleus by nuclear localization signal (NLS) to induce DNA fragmentation and chromatin condensation .
Furthermore, research has shown that endoplasmic reticulum (ER) is also involved in apoptosis. Redundant accumulation of proteins and disturbance of calcium homeostasis within ER can trigger ER stress and therefore apoptosis. Mouse bearing caspase-12 knock-out are resistant to apoptosis, indicative of caspase-12's involvement in ER-mediated apoptosis pathways . Caspase-12, which is located on the membrane of ER, is essential to ER-mediated apoptosis. ER response elicits caspase-12 expression while translocating cytoplasmic caspase-7 to ER membrane where caspase-12 is activated and apoptosis ensues .
Caspases are pivotal components of apoptosis (Table 1). To date, two types of caspases have been defined, the initiator caspase and effector/executioner caspase. As previously mentioned, caspase-8 and -9 are initiator caspases while caspase 3 is effector caspase. Furthermore, other caspases such as caspase-2, -10, and -11 belong to the initiator category while caspase-6 and -7 belong to the effector category [36,37].
Members of the Bcl-2 protein family are responsible for regulation of apoptosis . Two subgroups of this family perform opposite functions regarding apoptosis: they can be categorized as either pro-apoptotic or antiapoptotic (pro-survival). Table 2 illustrates the detailed classification and description of each member in the Bcl-2 family. In addition, p53 has been shown to regulate members of the Bcl-2 protein family . For example, p53 can directly induce transcription of Bax which is a pro-apoptotic protein .
As previously described, apoptosis is a highly controlled physiological process in multicellular organisms. Research on molecular mechanism of apoptosis reveals that anomalies in apoptosis lead to many diseases. Therefore, factors involved in apoptosis regulation are of tremendous diagnostic and intervention value in curing diseases .
Defective apoptosis is associated with many types of illness including autoimmune diseases, neurodegenerative diseases bacterial and viral diseases, heart diseases, and cancer [42,43].
Several reports have linked autoimmune diseases directly to dysregulated apoptosis and impaired clearance of apoptotic cells [44–49]. Rapid clearance of apoptotic cells is crucial to induce immunological tolerance and prevent inflammatory responses (Figure 1). Under physiological conditions, free apoptotic cells are rare in normal tissues [50–52]. However, inefficient ingestion of dying cells by phagocytes or increased rate of apoptosis can lead to secondary necrosis of free apoptotic cells, which induces secretion of pro-inflammatory cytokines. Autoantigens released from dying cells causes activation of T cell and expression of B cells, which generates autoantibodies and therefore autoimmunity (Figure 1). Many autoimmune diseases are consequences of impaired clearance of apoptotic cells such as systemic lupus erythematosus (SLE), connective tissue disease, and rheumatoid arthritis (RA) [53,54]. Defective apoptosis of immune cells can also cause autoimmune diseases such as multiple sclerosis and autoimmune lymphoproliferative syndromes [55,56]. Typically, the malfunctioning Fas/FasL apoptotic pathway interferes with normal apoptosis of lymphocytes leading to lymphocyte redundancy which in turn beget autoimmunity . Furthermore, experimental results have shown that mouse lacking Fas on T lymphocytes showed lupus-like symptoms and lymphocyte hyperplasia .
While dwindled apoptosis of immune cells facilitates autoimmunity and fosters autoimmune diseases, too much apoptosis is as well a pathological condition . Neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, and Parkinson's disease are all characterized by excessive apoptosis of neurons. For example, Alzheimer's disease is caused by accumulation of b-amyloids at lesion sites where b-amyloids induce abnormal apoptosis of neurons. Infections by HIV causes accelerated apoptosis CD4+ T cell, leading to onset of AIDS . Myocardial infarction is caused by acute apoptosis of myocytes .
To summarize, impaired clearance of apoptotic cells, and too little or too much apoptosis are both disease-prone. Thus tuning apoptosis to a balanced state can serve to treat diseases . If autoimmune lymphocytes cannot be cleared by apoptosis, these cells will attack autoantigens, triggering autoimmune diseases . Research has shown that repeated administration of autoantigens to individuals with autoimmune diseases can cure them by inducing apoptosis and therefore clearance of lymphocytes that specifically attack these autoantigens. Members of the Bcl-2 protein family have become important drug targets because their abnormal expression causes many diseases . Bcl-2, first member of its protein family and inhibitor of apoptosis, is pivotal to the occurrence and progression of cardiovascular diseases. A typical example is cardiac infarction which is caused by the lack of Bcl-2 expression and therefore excessive death of cardiomyocytes. Allowing overexpression of Bcl-2 in cardiomyocytes prevents apoptosis and has become an early stage therapeutic measure for cardiac infarction . Evasion of apoptosis has become a prerequisite for occurrence of tumor. Some tumors, like follicular lymphoma, are related to elevated expression of Bcl-2 which can be counteracted by RNA interference and treatment by antisense oligonucleotides. Topoisomerase inhibitors, antimetabolic agents and alkylating agents belong to the class of cytotoxic drugs whose efficacy is realized through apoptosis induction of tumor cells . For tumor cells expressing Fas, anti-Fas can specifically target these cells and induce rapid cell death. However, Fas is expressed on normal cells including peripheral while blood cells, T cells, and hepatocytes, therefore restricting the application of anti-Fas agonists. For apoptosis induced by cerebral ischemia, such as suffocation of newborns and cerebral ischemia in elderlies, along with Alzheimer's disease, retinal degeneration, transplant rejection, and neurodegenerative diseases are all caused by excessive apoptosis. Therefore, inhibiting caspases is an effective therapeutic plan . Cells undergo complex signaling pathways from apoptosis initiation to execution, involving a large network of proteins whereby blocking of any grid in the network can achieve therapeutic purpose . For example, nerve growth factors inhibit apoptosis and apparently suit therapeutic needs to diseases of extensive apoptosis; or increasing Bcl-2 expression which lowers neuron's sensitivity to apoptotic stimuli can inhibit pathological apoptosis of neurons in response to neurotoxic factors. Besides, small-molecule inhibitors of caspases, e.g., Z-VAD-FMK, has been proven useful in treating ALS in animals . For AIDS treatment, antiretrovirus drugs are major players in the market despite their low efficacy and severe side effects. If the therapeutic strategy shifts its focus to shielding T cells from apoptosis and combines T cell protection with retrovirus destruction, the outcome will become much more satisfactory. Moreover, chronic myocardial ischemia and hypoxia cause apoptosis of cardiomyocytes and cardiac fibroblasts, which is preventable and treatable by blocking apoptosis . In a word, designing treatment strategy based on the role of apoptosis in diseases associated with apoptosis anomalies holds great promises in restoring health and therefore is of critical research and application values (Table 3).
Clearance of apoptotic cells has been a major field of study in apoptosis-related researches. Efficient and timely clearance of apoptotic cells is crucial to avoid immune response to autoantigens and prevent perturbation to ambient cells and tissues . Majority of cells undergoing apoptosis are eliminated by phagocytes in the form of small vesicles known as ApoBDs. ApoBDs are relatively large vesicles compared with exosomes and microvesicles. ApoBDs have a diameter of 800–5000 nm while exosomes and microvesicles have a diameter of 30–100 and 50–1000 nm, respectively [87,88]. Furthermore, ApoBDs contain DNA, RNA, and proteins, similar to exosomes. However, the only marker of ApoBDs discovered so far is phosphatidylserine (PS) . Although definitive answer to the purpose of ApoBDs is currently absent, it is proposed that breakage into ApoBDs contribute to more efficient clearance of apoptotic cells and are important in controlling immune responses .
Breakage of apoptotic cells into ApoBDs was previously believed to be a random process until a recent discovery revealed that a well-coordinated process is responsible for the formation of ApoBDs. As shown in Figure 2, one of the earliest and most identifiable morphological changes is deformation of cells that appears as membrane blebbing. Formation of blebs is a result of increased hydrostatic pressure within the cell following contraction mediated by actomyosin . Notably, apoptotic blebs are distinct from necrotic blebs, which are generally larger, independent of actomyosin contraction, and are generated after membrane permeabilization . Repeated process of blebbing and retraction of apoptotic cells gives rise to formation of ApoBDs packed with organelles and other cellular contents such as chromatin . Another phenomenon known as apoptotic volume decrease (AVD) is also required for apoptotic body formation . Cytoskeletal disruption which inhibits AVD halts the formation of ApoBDs . AVD is an early event occurring concomitantly with membrane blebbing, leading to shrinkage of apoptotic cells. It is noteworthy that apoptotic blebs are different from necrotic blebs in many ways .
Patterns of apoptotic breakage into ApoBDs are illustrated in this figure. Majority of cells employ membrane blebbing, while some cells exhibit other types of membrane protrusions such as microtubule spikes, apoptopodia, and beaded apoptopodia.
It is now assumed that membrane blebbing is a prerequisite for apoptotic body formation . However, different cell types exhibit different forms of membrane deformation such as membrane protrusions including microtubule spikes, apoptopodia, and beaded apoptopodia . For example, neurons and some epithelial cells use microtubule spikes, instead of membrane blebbing, to form ApoBDs. Human jurkat T cells, primary mouse thymocyte, and fibroblasts forms apoptopodia following membrane blebbing, while apoptotic THP-1 cells and primary human neutrophils displayed beaded apoptopodia structure. It is notable that beaded apoptopodia appears to be the most efficient way of producing ApoBDs, generating approximately 10–20 ApoBDs at the same time . Beaded apoptopodia represents a unique mechanism of rapid formation of ApoBD. Interestingly, beaded apoptopodia and formation of ApoBDs were observed in neutrophils genetically engineered to be incapable of membrane blebbing, providing direct evidence that membrane blebbing is not required for formation of ApoBDs. Instead, other processes alone, or together with membrane blebbing, can promote disassembly of apoptotic cells and formation of ApoBDs. However, the detailed mechanism that ultimately rips cells into single ApoBD is still unclear. Researchers believe that a concerted effort of both intracellular and extracellular factors is required to shatter apoptotic cells into smaller vesicles and some unidentified force is there to separate membrane protrusions from the main cell body.
Clearance of ApoBDs has been a focus in apoptosis-related researches. Phagocytes recognize 'find-me' signals released by apoptotic cells and 'eat-me' signals on the ApoBDs to engulf them . Ingestion of cell corpses by phagocytes is termed efferocytosis as previously mentioned in the Introduction section. Efferocytosis is a four stage process that begins with locating the target cells . 'Find-me' signals, which are soluble mediators released by the apoptotic cells, mediate attraction of phagocytes to the vicinity of apoptotic cells. Release of soluble signals starts at the very beginning of apoptosis where a gradient is set up by these mediators . Signals are then recognized by receptors on the phagocytes, and triggers directional migration of phagocytes along the gradient towards ApoBDs. The second stage features 'Eat-me' signal recognition on ApoBDs. The 'eat-me' signals are represented by PS which becomes externalized and serves as signals for recognition and anchorage of phagocytes, allowing them to initiate the engulfing process . The third stage is engulfment. Cytoskeletal rearrangement and modification of the phagocytes occur to enable ingestion of ApoBDs . The last stage is digestion of cellular remnants through lysosomal degradation. The 'eat-me' signal PS can interact with a calcium phospholipid binding protein, Annexin V. Annexin V is a widely expressed protein belonging to the annexin superfamily. It is largely involved in blood coagulation due to its ability to bind PS . Therefore, Annexin V derivative has been developed to identify and image apoptosis [103–105].
Although ApoBDs can readily be engulfed by phagocytes, intact apoptotic cells can be engulfed just as effectively . In fact certain cell types do not fragment and form ApoBDs. However, in vitro studies showed that suppression of apoptotic blebbing, therefore formation of ApoBDs, impaired clearance of apoptotic cells by monocytes and macrophages [106,107].
Extracellular vesicles (e.g., exosomes and microvesicles) play a critical role in intercellular communications by transporting intracellular signaling molecules  Likewise, ApoBDs are vesicles that encapsulate residual ingredients of dying cells. Traditional views believed that apoptotic cells are phagocytosed to prevent deleterious impacts on the surroundings. A specific apoptotic body may contain a wide variety of cellular components, i.e., cytosol, degraded proteins, DNA fragments or even an intact organelle (Figure 3). An interesting question to ask is whether these cellular contents, are randomly distributed to each apoptotic body.
DNA, RNA, proteins, and cytokines are contained within ApoBDs. Transfer of macromolecules are mediated by ApoBDs upon engulfment of ApoBDs by recipient cells, in which contents of ApoBDs are released. Appropriate molecules released by ApoBDs commence downstream biological response or signaling pathways in recipient cells, therefore achieving the purpose of intercellular communication.
Recent studies have unraveled involvement of ApoBD in progression, metastasis, and formation of microenvironment of tumor. The discovery of ApoBD has offered new insights and explanations for physiological and pathological conditions. During the period of apoptosis, membrane blebbing promotes distribution of nuclear material into ApoBDs . Horizontal transfer of DNA can occur between adjacent whereas different types of cells. For example, DNA packaged into lymphoma-derived ApoBDs was engulfed by surrounding fibroblasts, resulting in the integration of lymphoma-derived DNA into the fibroblast genome . Transfer of oncogenes (h-ras and c-myc) by ApoBDs to recipient cells lacking p53 facilitates tumor formation . Apart from DNA, ApoBDs of endothelial cells mediate transfer of miRNA (i.e., miRNA-126) to healthy endothelial cells, and induce expression of a chemokine CXCL12 in recipient cells. In mouse models bearing atherosclerosis, repeated administration of ApoBDs containing miRNA-126 ameliorate the condition, at which this therapeutic effect may be mediated through induction of CXCL12 expression in luminal cells of aortic root plaques and recruitment of endothelial progenitor cells to repair blood vessels . Interestingly, DNA and RNA are packaged into ApoBDs of HL-60 cells, a type of granulocyte . Although the molecular mechanism is to be elucidated, an accumulation of reports has shown that functional molecules (i.e., DNA, RNA, and proteins) can indeed be packaged into ApoBDs, and different type of molecules follow different signaling pathways and therefore produce varied biological outcomes.
Apart from nucleotides, proteins can be transferred by ApoBDs to phagocytes, such as macrophages and DC cells, for immunoregulation. ApoBDs of thymocytes from BALB/c mouse are enriched with autoantigens and pro-inflammatory factors, along with 142 different protein including histones, hsp90, and many immunoproteins . Similarly, ApoBDs from lymphoblasts contain histones 1, 2A, 2B, 3, and 4, as well as autoantigen La/SSB 974. Shotgun proteomics identified 11 different proteins unique to ApoBDs of biliary epithelial cells as compared with their healthy counterparts . These proteins include Annexin A6, hsp6, LDL receptor-related proteins. These proteins are implicated in many immune pathways, e.g., activation of NF-κB, ERK, and Notch pathways, and signaling pathways mediated by IL8 and CXCR2. Recent studies also reported a drastic difference in 1028 proteins . Many research teams reported distribution of autoantigens into membrane vesicles and ApoBDs from a variety of cells (e.g., epithelial cells, T cells, cardiomyocytes) . It is noteworthy that human primary monocyte-derived macrophage can engulf ApoBDs containing autoantigens, suggesting a possible route through which autoantigens can be transferred to professional phagocytes . Furthermore, endothelial cells-derived ApoBDs contain precursor and processed pro-inflammatory factor IL-1α. ApoBDs containing IL-1α promote expression of chemokine IL-8 from healthy endothelial cells, thereby facilitating invasion of neutrophils into mouse peritoneum .
Contents of within the ApoBDs may be used for a number of purposes such as activation of immune system, recruitment of dying cells and regeneration of damaged tissues. Rubartelli et al. first reported that DC can selectively engulf ApoBDs . DC is a type of phagocytes capable of engulfing ApoBDs rich in auto-antigens. It is first reported in 1998 by Albert et al. that DCs acquire antigens from ApoBDs and induce class I-restricted CTLs . The same group later reported a continuation of this study that ApoBDs contain processed antigens that can be directly used by DCs for cross-presentation . In bone marrows, dying osteocytes release ApoBDs containing receptor activator of nuclear factor kappa-B ligand (RANKL) to recruit replacement osteoclasts .
Schiller and co-workers observed that immunogenic molecules enter ApoBDs in the early stage of apoptosis before DNA fragmentation . JAK1/STAT3 in hepatic stellate cells (HSC) pathway was activated through engulfment of ApoBDs derived from HepG2 cells, which also activated PI3K/Akt/NF-kB survival pathway to a lesser degree. Antiapoptotic proteins Mcl-1 and A1 were upregulated, leading to survival of HSC and spread of liver fibrosis . Marin-Gallen et al. recently revealed therapeutic capacity of ApoBDs . They reconstituted peripheral tolerance of type I diabetes by forced intake of in ApoBDs derived from in vitro cells by apoptosis-resistant DC cells. Therefore, these DC cells expressed lowered level of CD40 and CD86, and pro-inflammatory cytokines. As a result, autoimmunity against cells is reduced. These results suggest that ApoBDs can act as regulators at the cellular level and therefore possess conspicuous biological significance.
Furthermore, ApoBDs are carriers of contagious materials of pathogens. For example, ApoBDs of HIV-infected T cells can transfer proteins and genomic contents of HIV to adjacent epithelial cells where transcription and expression of viral proteins are furthered and assembly of HIV takes place . Besides, ApoBDs of prion-infected neurons must be effectively eliminated to prevent spreading of prions and onset of prion diseases .In mouse models bearing tumor xenografts, ApoBDs were detected in the blood . Moreover, murine fibroblasts lost contact inhibition and became tumorigenic after engulfing ApoBDs derived from cells transfected with oncogenes . These results suggest that genetic information can also be transferred by uptake of ApoBDs. Tumor cells release ApoBDs to environment upon apoptosis induced by treatments, which promotes tumor invasion and metastasis [127,130]. Hence, ApoBDs can function as a 'Trojan horse' for infectious agents .
To conclude, ApoBDs are messengers containing legacy of its progenitors, whose destiny lies far beyond being 'garbage bags' as we previously assumed. They can be recycled to initiate an array of biological responses. Further understanding of ApoBDs is essential to complete delineation of apoptosis.
The more efforts invested, the more we realize how complex the process of apoptosis is. It is a highly coordinated process of both morphological and biochemical change. Depending on the cell type and disassembly pattern, ApoBDs of different size and amount can be generated. Therefore, an obvious question can be asked: why the universal process of apoptosis can present itself in various ways? Why different cell types employ different ways of breakage? What controls the release, size and contents of ABs? By solving these mysteries, we become one step closer to complete understanding of programmed cell death under both physiological and pathological conditions. Lastly, it is encouraging that drugs that block or promote ApoBD formation have been advanced to the stage of clinical trials . Therefore, therapies and drugs designed based on regulation apoptosis and ApoBD formation hold great promises in curing intractable diseases .
This work was supported by the Chinese National Natural Sciences Foundation [grant numbers 81630092, 81773099, 81570790, 81573338]; the National Key R&D Research Program by Ministry of Science and Technology [grant numbers 2017YFA0506002, 2017YFA0104301]; the Shenzhen Science and Technology Innovation Committee [grant number JCYJ20160331152141936]; and Shenzhen Peacock Plan [grant number KQTD20140630165057031].


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ICYMI: Intel bug; early disclosure; counter-terror expo; Kaspersky; Macron
News by SC Staff
In Case You Missed It: Intel AMT bug; MS early disclosure spat; counter-terror expo; Kaspersky accused; Macron's DP.
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