Welcome to CollegeHighway.com
MyReminderService
Search CollegeHighway.com

Main Menu
  • Home

  • Event Calendar

  • College Critic

  • College Essays

  • New Music

  • News Topics

  • ProfessorRating

  • Recommend Us

  • Submit News

  • Top 10

  • My Account

  • FAQ


  • CollegeHighway.com Login
    Nickname

    Password

    Don't have an account yet? You can create one. As registered user you have some advantages like theme manager, comments configuration and post comments with your name.

    Free CollegeHighway WebMail
    Username:
    Password:


    Use Frames:
    Yes No

    Forgot Password URL
    Signup URL
    Help Section URL

    Toy Stores
    Looking for toy stores that sell every toy you could possibly want to buy? Check out this online toy store for cool toys like radio control cars, electric rc helicopters, and Hydro-Foam.

    Trippin?

    Book your flights and hotels online NOW!

    Check Yourself

    Aptitude, Entrepreneurship and Personality tests

    Ephemerids
    One Day like Today...


    Welcome
    You are Anonymous user. You can register for free by clicking here.

     
    Introduction
    Introduction

    You just clicked into the coolest place to get all your college news and information about college life. Looking to join the CollegeHighway crew? Click here.

     

    Marcos vs Duterte family feud drags both political dynasties’, and the Philippin
    Posted on Wednesday, April 17 @ 00:00:09 PDT (8 reads)
    College Guide Philippine president ferdinand marcos jnr’s tumultuous relationship with his predecessor rodrigo duterte is unlikely to improve, analysts say – and it could even worsen, given the firebrand ex-leader’s increasingly virulent attacks on his replacement. that the two men would clash was inevitable, according to jean encinas-franco, a political analyst from the university of the philippines diliman, because the alliance their families made in 2022 was “to win the election at any cost – and that’s it”. when asked about his relationship with the duterte family, marcos jnr admitted at a forum on tuesday: “it’s complicated”. speaking to the foreign correspondents association of the philippines, the president said: “the one i have the most contact with is [vice-president sara duterte] – and how we were during the election, [and since then] it hasn’t really changed.” the marcos and duterte families became allies in 2022 when sara, the daughter of ex-president duterte, joined marcos’ campaign in what proved to be a winning combination for both candidates. since then, the bond between the two clans has become increasingly fractious – with plenty of invective being hurled at the marcos family by the former president and his supporters. on monday, congressman pantaleon alvarez, a key duterte ally, called on the military to withdraw its support for marcos and force him to resign over his increasingly confrontational stance against beijing regarding their disputes in the west philippine sea – manila’s term for the section of the south china sea that outlines its maritime territory and includes its exclusive economic zone. “our constitution says the afp [armed forces of the philippines] shall protect the people and the state, not the president. If we allow the war to explode in the west philippine sea, there will be countless dead bodies and unimaginable destruction. Before that happens …. I call on the armed forces of the philippines to please withdraw your support to the chief executive …. [So he’ll step down],” alvarez said at a prayer rally in tagum city in the mindanao province of davao del norte on sunday. the philippine military said on tuesday that it plans to ask alvarez to explain his comments. The department of defence said it supports marcos jnr’s constitutional powers, adding calls for withdrawals of support might result in a “criminal investigation”. former congressman glenn chong, another staunch duterte supporter, claimed on monday at a separate rally that the 2022 election was rigged in marcos jnr’s favour. Chong said in march that he wanted to “slap” the president’s wife, louise “liza” araneta-marcos, claiming that all political appointments were being controlled by the philippine’s first lady. on social media, duterte’s supporters regularly assail marcos jnr as a weak leader. They also echo past accusations made by the former president that his successor was a cocaine user. during a press conference on thursday, duterte called marcos jnr a “crybaby” for his repeated criticisms of his predecessor’s policy on the west philippine sea, mocking the current president using obscenities and questioning whether he had finished college. in the face of such attacks, marcos jnr told the foreign correspondents’ forum he would he would not retaliate by handing duterte over to the international criminal court, which is currently investigating the former president for alleged crimes against humanity. Marcos jnr said the court has no jurisdiction in the philippines. philippines will not hand duterte to icc over drug war: president marcos jnr human rights organisations say duterte’s brutal war on drugs led to the indiscriminate murder of tens of thousands of filipinos, including children. during his visit to washington last week, marcos jnr addressed the philippine media’s questions about duterte’s insults, saying: “i don’t pay any attention to that. That means absolutely nothing to me … the former president is a highly experienced lawyer, he should know that ad hominem attacks like that really have no place.” his comments came as his working relationship with vice-president sara duterte appears to have grown increasingly tense in recent years. after the election in 2022, sara indicated that she wanted to be defence secretary but was given the education portfolio instead. When she requested 650 million philippine pesos (us$11.5 million) in “confidential funds” last year for her office’s discretionary use, she faced intense criticism and withdrew her request. It was later revealed that she had received 125 million pesos in confidential funds in 2022, spending the entire amount in 11 days. She was again pilloried, but marcos jnr did not defend her. the current philippine president has also seemingly snubbed his no 2 at several recent public events, and has not intervened to help pastor apollo quiboloy – a spiritual adviser and ally of the ex-president – who is being investigated by american and philippine law enforcers for alleged sex trafficking. despite his non-confrontational approach, marcos jnr has occasionally hit back. Early this year, after duterte repeated his claim at a rally that the president was a drug addict, marcos jnr responded by speculating whether his foul-mouthed predecessor was ranting under the influence of fentanyl. marcos jnr has also criticised duterte over a recent revelation that the previous administration reached an unwritten agreement with chinese president xi jinping to maintain the status quo in the south china sea. He said he was “horrified” over the agreement and questioned why it was kept secret from him and others. “they call it a gentleman’s agreement, i call it a secret agreement”, he told reporters in washington. in the foreign correspondents’ forum on tuesday, marcos jnr said in comments directed at duterte: “we still have to find out what this is all about. I tried to ask officials of the former administration [but] i haven’t got a straight answer … what is contained in that agreement and what did we agree to? Why do you keep it secret?” he had not been able to get answers about the agreement because of “many excuses”, the philippine president said. people hungry for absolute power never really work well together. One side has to win nuelle duterte, ex-president rodrigo duterte’s niece rumours of the agreement prompted duterte to hold a press conference to discuss the matter, with his admission of its existence sparking accusations of treason. franco, the political analyst, said she could not foresee any type of reconciliation between marcos jnr, duterte and their families. “I think there is already so much distrust, so it is difficult to patch things up,” she said. nuelle duterte, the former president’s niece who has long been a critic of her uncle’s administration, told this week in asia that even during the 2022 campaign, she “didn’t think this unity would last, mostly because people hungry for absolute power never really work well together. One side has to win.” the new zealand-based psychiatrist said the two families had to enter the alliance in 2022 because they would have lost the election otherwise. “it was a strategic alliance, nothing more. Will it last? Likely no, because neither party wants to be the subordinate of the other.”
    ( Read More... | 14898 bytes more | comments? | Printer Friendly Page  Send this Story to a Friend )

     
    List of episodes by production order
    Posted on Wednesday, April 17 @ 00:00:09 PDT (8 reads)
    College Guide | mno edit summary | mno edit summary |line 3,938: |line 3,938: | | 35abf08 | | 35abf08 | |765 - 36?? | |765 - 36?? |? | |2024 |+ | |2024 | |[[the yellow lotus]] | |[[the yellow lotus]] | |- | |- |line 3,947: |line 3,947: | |- | |- | |35abf10 | |35abf10 |? | |767 - |+ | |767 - |? | |2024 |+ | |2024 | |[[the tell-tale pants]] | |[[the tell-tale pants]] | |- | |- | |35abf11 | |35abf11 | |768 - 35?? | |768 - 35?? |? | |2024 |+ | |2024 | |[[the tipping point]] | |[[the tipping point]] | |- | |- | |35abf12 | |35abf12 | |769 - 35?? | |769 - 35?? |? | |2024 |+ | |2024 | |[[barts brain]] | |[[barts brain]] | |- | |- | | 35abf13 | | 35abf13 | |770 - 36?? | |770 - 36?? |? | |2024 |+ | |2024 | |tba | |tba | |- | |- | |35abf14 | |35abf14 | |771 - 36?? | |771 - 36?? |? | |2024 |+ | |2024 | |tba | |tba | |- | |- | |35abf15 | |35abf15 | |772 - 36?? | |772 - 36?? |? | |2024 |+ | |2024 | |tba | |tba | |- | |- latest revision as of 01:08, 17 april 2024 a production code is an identity for each and every simpsons episodes assigned by the production team to help identify it from its respective season/episode number. Episodes are often broadcast by their production order i.E. In numerical order. This is a list of the simpsons episodes by production order, along with their broadcast season/episode numbers, and their original broadcast dates. for the list of episodes by date, see here and for the list of episodes in alphabetical order, see https://simpsons.Fandom.Com/wiki/category:episodes. production codes |prod. Code |prod. Season |episodes |holdovers |7g | 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 notes - the simpsons uses the same production code format as other 20th century fox-produced shows. It has received three revisions over the shows run: [[1]]https://simpsons.Fandom.Com#cite_note-1 - the first, used before 1990, was formatted ssxx: ss denoting the randomly-chosen season identifier for any show, usually consisting of a number and letter, with xx being the order in which the episode was produced. Season 1 of the simpsons was given the identification 7g, which was used as an in-joke by james l. Brooksby having homer simpsonwork in sector 7g at the springfield nuclear power plant. - the second, used from 1990 until 1998, was formatted ysxx: y was the identifier for the television season that it was produced for (i.E. 7 for the 1990-91 tv season until 5 for 1997-98), s being the letter given to the show in question (e.G. F for the simpsons, x for the x-files) and xx being the order in which the episode was produced. The simpsons used this code format from seasons 2 until 9, including season 4s 9f being succeeded by season 5s 1f. The number 6 was not used as this format was replaced after the digit 5 was available. - the third and most recent has been used since 1998. It is currently formatted as 0sssxx, with 0 being the season identifier from 1 to z (excluding i because it can be confused with numerical digits and u for unknown reasons), sss is the three-letter identifier for the show in question (e.G. Shows held over from the previous tv season had their existing identifier prefixed with ab, meaning the simpsons uses abf) and xx being the order in which the episode was produced. The simpsons started using this code at season 10, so it was given the digit a. Regarding discrepancies, season 18 used the letter j, following season 17s h, which is also true for seasons 22 and 23s n and p, and seasons 26 and 27s t and v. - season 24 additionally skipped the letter q and instead used r. After season 31 concluded with z, the originally-unavailable q was assigned to season 32. - season 33 has been assigned the originally-unavailable u. - season 34 has been assigned the originally-unavailable o. - season 35 has been given 35abf as the production code. - the first, used before 1990, was formatted ssxx: ss denoting the randomly-chosen season identifier for any show, usually consisting of a number and letter, with xx being the order in which the episode was produced. Season 1 of the simpsons was given the identification 7g, which was used as an in-joke by - the 3g production code refers to the supplemental set of episodes produced within the 7th production season under al jean& mike reiss(previously showrunners for seasons 3 and 4) as showrunners, despite that bill oakley& josh weinsteinwere the main showrunners of seasons 7 and 8. Four episodes were produced from 3g01-04, the springfield files, lisas sax, simpsoncalifragilisticexpiala(annoyed grunt)cious and simpson tide, respectively. 3g01 and 3g03 were both aired in season 8 while 3g02 and 3g04 were both aired in season 9. - holdovers are episodes that eventually air on a succeeding season that was produced within an earlier production season, e.G. Season 4 has the code 9f, but the two episodes at the start of the season use 8f as they were initially produced for season 3. The 19th production season has the most number of holdovers, as nine episodes from the season aired during the 20th broadcast season. 7g - season 1 |prod. Code |episode no. |airdate |title |7g01 |1 - 113 |may 13, 1990 | bart the genius homers odyssey theres no disgrace like home bart the general moaning lisa the telltale head simpsons roasting on an open fire the call of the simpsons homers night out life on the fast lane krusty gets busted the crepes of wrath 7f - season 2 |prod. Code |episode no. |airdate |title |7f01 |14 - 204 |november 1, 1990 | simpson and delilah bart gets an f treehouse of horror dancin homer bart the daredevil bart vs. Thanksgiving dead putting society itchy & scratchy & marge bart gets hit by a car one fish, two fish, blowfish, blue fish the way we was homer vs. Lisa and the 8th commandment barts dog gets an f principal charming oh brother, where art thou? Old money brush with greatness lisas substitute the war of the simpsons three men and a comic book blood feud when flanders failed stark raving dad 8f - season 3 |prod. Code |episode no. |airdate |title |8f01 |38 - 302 |september 26, 1991 | treehouse of horror ii bart the murderer homer defined like father, like clown lisas pony saturdays of thunder flaming moes burns verkaufen der kraftwerk i married marge radio bart lisa the greek homer at the bat homer alone separate vocations bart the lover dog of death a streetcar named marge colonel homer black widower the otto show barts friend falls in love brother, can you spare two dimes? Kamp krusty 9f - season 4 |prod. Code |episode no. |airdate |title |9f01 |62 - 403 |october 8, 1992 | lisa the beauty queen itchy & scratchy: the movie treehouse of horror iii marge gets a job new kid on the block mr. Plow lisas first word homers triple bypass marge vs. The monorail selmas choice brother from the same planet i love lisa duffless last exit to springfield the front so its come to this: a simpsons clip show whacking day krusty gets kancelled marge in chains homers barbershop quartet cape feare 1f - season 5 |prod. Code |episode no. |airdate |title |1f01 |84 - 504 |october 21, 1993 | homer goes to college marge on the lam treehouse of horror iv barts inner child boy-scoutz n the hood the last temptation of homer $pringfield (or, how i learned to stop worrying and love legalized gambling)) homer the vigilante homer and apu bart gets famous lisa vs. Malibu stacy deep space homer homer loves flanders bart gets an elephant burns heir lisas rival sweet seymour skinners baadasssss song the boy who knew too much secrets of a successful marriage lady bouviers lover bart of darkness 2f - season 6 |prod. Code |episode no. |airdate |title |2f01 |106 - 604 |october 2, 1994 | sideshow bob roberts treehouse of horror v barts girlfriend lisa on ice homer badman grampa vs. Sexual inadequacy fear of flying homer the great and maggie makes three barts comet homie the clown bart vs. Australia homer vs. Patty and selma lisas wedding who shot mr. Burns? (Part one)) radioactive man two dozen and one greyhounds the pta disbands who shot mr. Burns? (Part two)) the springfield connection lemon of troy a star is burns round springfield another simpsons clip show 3f/3g - season 7 |prod. Code |episode no. |airdate |title |3f01 |131 - 703 |october 1, 1995 | bart sells his soul lisa the vegetarian treehouse of horror vi king-size homer mother simpson marge be not proud sideshow bobs last gleaming two bad neighbors team homer scenes from the class struggle in springfield bart the fink lisa the iconoclast homer the smithers a fish called selma the day the violence died bart on the road 22 short films about springfield raging abe simpson and his grumbling grandson in the curse of the flying hellfish much apu about nothing homerpalooza summer of 4 ft. 2 you only move twice el viaje misterioso de nuestro jomer (the mysterious voyage of homer)) the simpsons 138th episode spectacular the springfield files lisas sax simpsoncalifragilisticexpiala(annoyed grunt)ciouscious) simpson tide 4f - season 8 |prod. Code |episode no. |airdate |title |4f01 |160 - 807 |december 15, 1996 | treehouse of horror vii the homer they fall a milhouse divided burns, baby burns bart after dark hurricane neddy the twisted world of marge simpson grade school confidential mountain of madness homers phobia the itchy & scratchy & poochie show my sister, my sitter brother from another series homer vs. The eighteenth amendment the canine mutiny the old man and the lisa in marge we trust homers enemy the simpsons spin-off showcase the secret war of lisa simpson the city of new york vs. Homer simpson the principal and the pauper lisa the simpson 5f - season 9 |prod. Code |episode no. |airdate |title |5f01 |184 - 905 |november 2, 1997 | treehouse of horror viii bart star the two mrs. Nahasapeemapetilons lisa the skeptic realty bites miracle on evergreen terrace bart carny trash of the titans the last temptation of krust das bus dumbbell indemnity this little wiggy the trouble with trillions girly edition king of the hill lost our lisa natural born kissers when you dish upon a star lard of the dance the wizard of evergreen terrace bart the mother the joy of sect all singing, all dancing aabf - season 10 |prod. Code |episode no. |airdate |title |aabf01 |208 - 1004 |october 25, 1998 | doh-in in the wind lisa gets an a homer simpson in: kidney trouble mayored to the mob viva ned flanders wild barts cant be broken sunday, cruddy sunday homer to the max marge simpson in: screaming yellow honkers im with cupid make room for lisa maximum homerdrive simpsons bible stories mom and pop art the old man and the c student monty cant buy me love they saved lisas brain e-i-e-i-doh thirty minutes over tokyo guess whos coming to criticize dinner? Brothers little helper beyond blunderdome babf - season 11 |prod. Code |episode no. |airdate |title |babf01 |231 - 1104 |october 31, 1999 | hello gutter, hello fadder eight misbehavin little big mom take my wife, sleaze faith off grift of the magi the mansion family saddlesore galactica alone again, natura-diddily missionary: impossible pygmoelian bart to the future days of wine and dohses last tap dance in springfield kill the alligator and run insane clown poppy its a mad, mad, mad, mad marge behind the laughter a tale of two springfields treehouse of horror xi hom? cabf - season 12 |prod. Code |episode no. |airdate |title |cabf01 |253 - 1204 |november 19, 2000 | the computer wore menace shoes the great money caper homer vs. Dignity pokey mom skinners sense of snow tennis the menace worst episode ever hungry, hungry homer day of the jackanapes bye bye nerdie new kids on the blecch simpson safari trilogy of error im goin to praiseland children of a lesser clod simpsons tall tales a hunka hunka burns in love treehouse of horror xii homer the moe the blunder years the parent rap dabf - season 13 |prod. Code |episode no. |airdate |title |dabf01 |275 - 1307 |january 6, 2002 | she of little faith sweets and sour marge half-decent proposal jaws wired shut the bart wants what it wants the lastest gun in the west tales from the public domain the old man and the key blame it on lisa weekend at burnsies gump roast i am furious (yellow)) the sweetest apu little girl in the big ten the frying game poppas got a brand new badge large marge treehouse of horror xiii bart vs. Lisa vs. The third grade helter shelter how i spent my strummer vacation eabf - season 14 |prod. Code |episode no. |airdate |title |eabf01 |297 - 1406 |december 15, 2002 | special edna the dad who knew too little the strong arms of the ma barting over pray anything im spelling as fast as i can a star is born-again mr. Spritz goes to washington c.E. Doh scuse me while i miss the sky three gays of the condo dude, wheres my ranch? Old yeller-belly brake my wife, please the bart of war moe baby blues my mother the carjacker the fat and the furriest the president wore pearls treehouse of horror xiv the regina monologues fabf - season 15 |prod. Code |episode no. |airdate |title |fabf01 |319 - 1506 |december 7, 2003 | tis the fifteenth season marge vs. Singles, seniors, childless couples and teens and gays i, (annoyed grunt)-bot-bot) diatribe of a mad housewife margical history tour milhouse doesnt live here anymore the ziff who came to dinner smart and smarter co-dependents day the wandering juvie my big fat geek wedding the way we werent catch em if you can simple simpson midnight rx bart-mangled banner fraudcast news sleeping with the enemy alls fair in oven war fat man and little boy she used to be my girl treehouse of horror xv gabf - season 16 |prod. Code |episode no. |airdate |title |gabf01 |342 - 1607 |january 30, 2005 | homer and neds hail mary pass pranksta rap theres something about marrying on a clear day i cant see my sister goo goo gai pan mobile homer the seven-beer snitch the father, the son and the holy guest star dont fear the roofer the heartbroke kid future-drama a star is torn thank god its doomsday home away from homer the girl who slept too little treehouse of horror xvi the bonfire of the manatees milhouse of sand and fog marges son poisoning see homer run the last of the red hat mamas habf - season 17 |prod. Code |episode no. |airdate |title |habf01 |364 - 1709 |december 18, 2005 | the italian bob homers paternity coot were on the road to doh-where my fair laddy the seemingly never-ending story bart has two mommies homer simpson, this is your wife million-dollar abie kiss kiss bang bangalore the wettest stories ever told girls just want to have sums regarding margie the monkey suit the mook, the chef, the wife and her homer marge and homer turn a couple play treehouse of horror xvii jazzy and the pussycats moena lisa please homer, dont hammer em g.I. (Annoyed grunt)) ice cream of margie (with the light blue hair)) jabf - season 18 |prod. Code |episode no. |airdate |title |jabf01 |388 - 1809 |december 17, 2006 | the haw-hawed couple the wife aquatic little big girl revenge is a dish best served three times homerazzi springfield up rome-old and julie-eh yokel chords marge gamer the boys of bummer stop or my dog will shoot! Crook and ladder 24 minutes you kent always say what you want treehouse of horror xviii husbands and knives the homer of seville i dont wanna know why the caged bird sings he loves to fly and he dohs midnight towboy little orphan millie kabf - season 19 |prod. Code |episode no. |airdate |title |kabf01 |408 - 1908 |november 25, 2007 | eternal moonshine of the simpson mind e. Pluribus wiggum that 90s show love, springfieldian style the debarted dial n for nerder smoke on the daughter papa dont leech apocalypse cow any given sundance mona leaves-a all about lisa double, double, boy in trouble lost verizon treehouse of horror xix sex, pies, and idiot scrapes dangerous curves homer and lisa exchange cross words mypods and boomsticks the burns and the bees lisa the drama queen labf - season 20 |prod. Code |episode no. |airdate |title |labf01 |430 - 2010 |february 15, 2009 | how the test was won no loan again, naturally gone maggie gone wedding for disaster eeny teeny maya, moe the good, the sad and the drugly father knows worst four great women and a manicure waverly hills, 9-0-2-1-doh in the name of the grandfather coming to homerica homer the whopper treehouse of horror xx bart gets a z the great wife hope the devil wears nada pranks and greens rednecks and broomsticks once upon a time in springfield the simpsons 20th anniversary special – in 3-d! On ice! mabf - season 21 |prod. Code |episode no. |airdate |title |mabf01 |450 - 2108 |december 13, 2009 | thursdays with abie million dollar maybe postcards from the wedge boy meets curl the color yellow stealing first base american history x-cellent chief of hearts the greatest story ever dohed the bob next door to surveil with love moe letter blues the squirt and the whale judge me tender treehouse of horror xxi loan-a lisa moneybart donnie fatso lisa simpson, this isnt your life elementary school musical the fight before christmas nabf - season 22 |prod. Code |episode no. |airdate |title |nabf01 |472 - 2206 |november 21. 2010 | how munched is that birdie in the window? Moms id like to forget flaming moe homer the father the blue and the gray angry dad: the movie the scorpions tale a midsummers nice dream love is a many strangled thing the great simpsina the real housewives of fat tony homer scissorhands 500 keys the ned-liest catch the falcon and the dohman bart stops to smell the roosevelts holidays of future passed treehouse of horror xxii the food wife replaceable you the book job pabf - season 23 |prod. Code |episode no. |airdate |title |pabf01 |494 - 2307 |november 27, 2011 | the ten-per-cent solution politically inept, with homer simpson the doh-cial network moe goes from rags to riches the daughter also rises at long last leave how i wet your mother exit through the kwik-e-mart them, robot beware my cheating bart a totally fun thing that bart will never do again the spy who learned me lisa goes gaga ned n ednas blend gone abie gone treehouse of horror xxiii adventures in baby-getting penny-wiseguys the day the earth stood cool moonshine river rabf - season 24 |prod. Code |episode no. |airdate |title |rabf01 |516 - 2408 |december 16, 2012 | homer goes to prep school a test before trying changing of the guardian hardly kirk-ing gorgeous grampa love is a many-splintered thing what animated women want black-eyed, please dark knight court pulpit friction whiskey business the fabulous faker boy the saga of carl the man who came to be dinner treehouse of horror xxiv dangers on a train four regrettings and a funeral labor pains homerland brick like me yolo sabf - season 25 |prod. Code |episode no. |airdate |title |sabf01 |538 - 2508 |december 15, 2013 | the kid is all right married to the blob yellow subterfuge steal this episode specs and the city the man who grew too much diggs the winter of his content the war of art you dont have to live like a referee luca$ days of future future what to expect when barts expecting pay pal simpsorama the wreck of the relationship the yellow badge of cowardge super franchise me clown in the dumps treehouse of horror xxv opposites a-frack tabf - season 26 |prod. Code |episode no. |airdate |title |tabf01 |560 - 2607 |november 16, 2014 | covercraft i wont be home for christmas the musk who fell to earth barts new friend walking big & tall my fare lady the princess guide sky police waiting for duffman peeping mom the kids are all fight lets go fly a coot every mans dream bull-e mathletes feat cue detective treehouse of horror xxvi puffless lisa with an s friend with benefit halloween of horror vabf - season 27 |prod. Code |episode no. |airdate |title |vabf01 |582 - 2708 |december 6, 2015 | barthood the girl code teenage mutant milk-caused hurdles much apu about something gal of constant sorrow love is in the n2-o2-ar-co2-ne-he-ch4 lisa the veterinarian the marge-ian chronicles the burns cage how lisa got her marge back fland canyon simprovised to courier with love orange is the new yellow treehouse of horror xxvii the town friends and family havana wild weekend monty burns fleeing circus trust but clarify there will be buds wabf - season 28 |prod. Code |episode no. |airdate |title |wabf01 |604 - 2808 |november 20, 2016 | the nightmare after krustmas the last traction hero the great phatsby: part one the great phatsby: part two pork and burns fatzcarraldo the cad and the hat kamp krustier 22 for 30 a fathers watch the caper chase looking for mr. Goodbart moho house dogtown whistlers father the serfsons treehouse of horror xxviii grampy can ya hear me the old blue mayor she aint what she used to be singin in the lane springfield splendor xabf - season 29 |prod. Code |episode no. |airdate |title |xabf01 |626 - 2908 |december 3, 2017 | gone boy haw-haw land frink gets testy 3 scenes plus a tag from a marriage homer is where the art isnt no good read goes unpunished fears of a clown forgive and regret king leer lisa gets the blues left behind throw grampa from the dane flanders ladder heartbreak hotel treehouse of horror xxix my way or the highway to heaven baby you cant drive my car barts not dead from russia without love werking mom krusty the clown (episode)) yabf - season 30 |prod. Code |episode no. |airdate |title |yabf01 |648 - 3009 |december 2, 2018 | tis the 30th season mad about the toy the girl on the bus the clown stays in the picture im dancing as fat as i can 101 mitigations i want you (shes so heavy)) e my sports bart vs. Itchy & scratchy girls in the band im just a girl who cant say doh the incredible lightness of being a baby doh canada woo-hoo dunnit? Crystal blue-haired persuasion thanksgiving of horror treehouse of horror xxx the winter of our monetized content gorillas on the mast go big or go homer the fat blue line zabf - season 31 |prod. Code |episode no. |airdate |title |zabf01 |670 - 3110 |december 15, 2019 | marge the lumberjill livin la pura vida todd, todd, why hast thou forsaken me hail to the teeth the miseducation of lisa simpson frinkcoin bart the bad guy screenless highway to well better off ned) warrin priests: part one warrin priests: part two the hateful eight-year-olds the 7 beer itch the way of the dog treehouse of horror xxxi i, carumbus undercover burns the road to cincinnati now museum, now you dont) podcast news qabf - season 32 |prod. Code |episode no. |airdate |title |qabf01 |692 - 3209 |december 6, 2020 | three dreams denied a springfield summer christmas for christmas the dad-feelings limited diary queen wad goals yokel hero do pizzabots dream of electric guitars? Manger things uncut femmes burger kings panic in the streets of springfield the man from g.R.A.M.P.A. Mother and child reunion the last barfighter treehouse of horror xxxii the star of backstage barts in jail! The wayz we were lisas belly a serious flanders (part one)) a serious flanders (part two)) uabf - season 33 |prod. Code |episode no. |airdate |title |uabf01 |714 - 3308 |november 21, 2021 | mothers and other strangers a made maggie pixelated and afraid the longest marge boyz n the highlands you wont believe what this episode is about - act three will shock you! Bart the cool kid pretty whittle liar the sound of bleeding gums my octopus and a teacher girls just shauna have fun meat is murder poorhouse rock marge the meanie habeas tortoise not it treehouse of horror xxxiii one angry lisa the king of nice lisa the boy scout step brother from the same planet oabf- season 34 |prod. Code |episode no. |airdate |title |oabf01 |736 - 3407 |november 13, 2022 | when nelson met lisa game done changed top goon my life as a vlog the many saints of springfield carl carlson rides again bartless hostile kirk place pin gal fan-ily feud write off this episode homers adventures through the windshield glass the very hungry caterpillars clown v. Board of education a mid-childhood nights dream treehouse of horror xxxiv homers crossing its a blunderful life mcmansion & wife thirst trap: a corporate love story iron marge 35abf- season 35 |prod. Code |episode no. |airdate |title |35abf01 |758 - 3510 |december 24, 2023 |
    ( Read More... | 48304 bytes more | comments? | Printer Friendly Page  Send this Story to a Friend )

     
    How education and social media regulation can combat science denial
    Posted on Wednesday, April 17 @ 00:00:09 PDT (8 reads)
    College Guide It’s ironic that as scientific evidence on climate change and vaccines have become more compelling, public opinion on social media appears more divided. five billion people use social media globally, and millions of posts are shared on meta (facebook) every minute. while a virtual life can be fun and informative, it can also be harmful. Misinformation about climate science is rife . So, too are conspiracy theories and disinformation about vaccine science, as we witnessed during the covid-19 pandemic. this misinformation not only undermines trust in science but actively threatens public health: the world health organization has named vaccine hesitancy, along with air pollution and climate health, among the top 10 global health threats of our time. the evidence shows that vaccines save lives, and that climate change is strongly linked to rising water temperatures, sea level rise, shrinking polar ice caps, loss of biodiversity and more extreme weather events. 2023 was the hottest year on record . Greenhouse gas emissions hit record highs. The earth is sounding its distress call. but ironically, as the scientific evidence has become more compelling, public opinion appears to be more divided. this hesitancy and denial appear to be founded in a misconception of how science works. vaccines save millions of lives every year, and with improved technology, the accepted view on climate change has changed, with unequivocal data showing increases in co2 and higher temperatures are linked to the burning of fossil fuels. this is science in action. but opponents on social media, and other outlets, claim the scientific evidence for both is undecided and conflicting. Oppositional viewpoints are often supported by a few vocal scientists in white coats spreading misinformation, uncertainty and doubt. the fossil fuel industry also plays a part in undermining science, by emphasising this so-called “dissent” within the scientific community. this tactic is not new: for decades, the industry has created shell organisations and companies to fund climate science-denial and muddy public understanding of climate science. more recently, the fossil fuel industry and other major polluters have used social media to gain new audiences. One analysis found that 16 of the world’s biggest polluters were responsible for placing more than 1700 false and misleading ads on facebook in 2021. there will always be a few scientists who challenge the accepted view. However, more than 97 percent of professional medical and climate scientists, having reviewed the existing evidence, agree that vaccines are safe, and that human activity is increasing co2 and warming the earth’s surface. the key message the public needs to hear is: what matters is the preponderance of evidence, not one person’s opinion. facts are considered true because they are based on the preponderance of evidence, whereas opinions may be true or not . it is easy to see how social media — which platforms opinions and untruths, and does away with traditional gatekeepers of knowledge such as news editors — can facilitate an impression that the science around climate change and vaccines is unsettled or “controversial.” this is especially the case because 80 percent of social media platforms do not have a content moderation policy that includes a comprehensive, universal definition of climate misinformation, according to a september 2023 report by the climate action against disinformation coalition. artificial intelligence (ai) can further support high quality oppositional opinions in new ways to deceive and cast doubt. ai algorithms can mean someone who clicks on one anti-vax post is then fed a steady diet of anti-vax and other anti-science content. Similarly, ai can be used to target misinformation to vulnerable audience sectors. And ai programs trained to write text using vast data sets have automated fake news generation with increased persuasive potential. change begins with education bridging the consensus gap between science believers and deniers requires education. learning about the scientific method is important, but — in an age of conspiracy theories, misinformation and “alternative facts” — so too is critical literacy and philosophical inquiry. broadening school curricula to help students navigate complex ideas and virtual digital realities, and to make sense of their increasingly complex world, could help. since children engage with social media from a young age, it makes sense for our education system to help them develop new skills in assessing truths and falsehoods when confronted with new information. education from preschool to year 12 could include age-appropriate exercises on conspiracies commonly discussed on social media, ranging from vaccination scare tactics, to climate denialism, to flat earth theory, to claims the moon landing was a hoax, and the earth is 6000 years old. if started early enough, this education could align with a child’s development and transitioning thinking skills from concrete representational to more abstract learning, a process that begins around six years old . a “world social media organisation” could be a solution social media platforms have been essentially permitted to self-regulate for decades. That’s a problem, because they can make money off companies that pay to promote “fake news” and other forms of anti-science misinformation. there have been some moves to regulate social media platforms in recent years, with varying degrees of success. in mid-2023, the australian government proposed legislation that would boost the powers of the australian communications and media authority to pressure tech companies into fighting online misinformation . But the draft bill hasn’t passed , and australia remains in the early stages of responding to fake news and disinformation. individual platforms have their own mechanisms to reduce misinformation. for example, x (formerly twitter) has introduced a “community notes” feature where under misinformation tweets you can see “readers added context” with the corrected facts. but x has been named as the worst offender in terms of spreading climate misinformation, according to the 2023 climate action against disinformation coalition report . Meta, tiktok and youtube, despite having commitments to address climate misinformation on their platforms, are lacking on policy enforcement. rather than relying on governments to pass laws in isolation — or expecting social media platforms to effectively regulate themselves — some form of international regulation is urgently required to prevent the constant barrage of misinformation and harm pervading the online world. project liberty , formed in 2021, has mobilised a global alliance of technologists, academics, policymakers and citizens to build a safer, healthier internet and social media. The organisation supports work on misinformation flagging, interventions to reduce deepfakes, and teaching online news. the european commission has also tackled online disinformation with a high-level group of experts who made key recommendations, including developing tools for educating platform users. in 2018, an international grand committee on disinformation comprising the uk, argentina, belgium, brazil, canada, france, ireland, latvia and singapore — met for the first time. The committee has since met in ottawa and dublin, and co-hosted a series of seminars in the us. these initiatives are a start. They show that cross-border collaboration on tackling the global problem of internet disinformation is possible. but given the magnitude of the disinformation problem — especially with growing concerns around ai — the international community needs to go one step further. social media companies should be no different from global drug companies which are tightly regulated, for example, by the fda and tga, to produce drugs for humans that cause no harm. one solution could be the formation of a world social media organisation, comprising world partners from each country, to oversee harmful content. like the who to support global health, the organisation could be dedicated to advancing the responsible dissemination of knowledge, and preventing harm and hate speech, to promote the wellbeing of society. in today’s society, where digital information is ubiquitous, and changing rapidly, we need to embrace robust debate, listen to the experts, verify what they say, understand the methods they used, and not be swayed by the uninformed or naysayers. we need to be digital citizens protecting our rights, not digital subjects being manipulated by social media. if society fails to regulate social media, historians 100 years from now may write: “the people of the early 21st century became so overwhelmed with digital information that they failed to develop the skills and systems to sufficiently process its content to the detriment of their society”. dr geoffrey dobson is a professor in the college of medicine and dentistry and australian institute of tropical health & medicine at james cook university in townsville. He holds a professorial chair in the heart, trauma and sepsis research laboratory. originally published under creative commons by 360info ™.
    ( Read More... | 18602 bytes more | comments? | Printer Friendly Page  Send this Story to a Friend )

     
    Top 7 strategies for spotting a STAGED EVENT within the first 72 hours
    Posted on Wednesday, April 17 @ 00:00:09 PDT (8 reads)
    College Guide 1 1 09:56 pm #1 top 7 strategies for spotting a staged event within the first 72 hours top 7 strategies for spotting a staged event within the first 72 hours 04/15/2024 // s.D. Wells// 4k views tags: 9/11, awakening, big government, cia, conspiracy, deception, deep state, disinfo, fact check, fake news, faked, false-flag, fbi corruption, journalism, lies, mainstream media, plandemic, propaganda, resist, rigged, scamdemic, staged events, staged war, terrorism, tips, tyranny, vietnam whether they are vying for control of the populace, taking their guns away, scaring them into forfeiting more constitutional rights, relinquishing all medical freedoms or simply declaring a fake war for political purposes (laundering and embezzling billions of dollars), the u.S. Government stops at nothing to plan, stage, carry out and propagandize staged events.Some are real. Some are partially real. Some are nearly completely fake. Often these are set up and rigged by the fbi, cia or other government entities. The media-brainwashed populace calls people who dont trust these events and their narratives conspiracy theorists, but you are actually a conspiracy theorist if you do believe the fake news (all of mainstream media, social media, google, youtube and the sold-out newspapers). how to spot the tell-tale signs of a government-backed staged event #1. All of mass media has the same story from the outset. #2. Nothing seems to add up to the official story at all, as the so-called facts keep getting dismantled by truth media. #3. Always start with the guilty until proven innocent approach, because nearly every major catastrophe over the past two-and-a-half decades has been staged. #4. Mass media blames the russians. #5. Right after the event happens, politicians and media pundits demand u.S. Citizens back gun control (gun-grabbing) legislation or taxpayer funding for another proxy war. #6. The catastrophe cripples the supply chain of food and/or fuel that opposes the democrats plan of complete government control through green living. #7. The event helps the government take away constitutional rights, medical freedom of choice and further empowers police-state tyranny. the sheeple that believes staged events arent inside jobs are all brainwashed by fluoride, vaccines, pharmaceuticals, processed food, fake news during the vietnam war, the u.S. Government had the majority of the populace believing we were winning the war, by using propaganda about communist aggression and falsified statistics about how many soldiers were coming home in body bags or without arms or legs. It was a complete horror story and a war that was impossible to win, in a jungle full of landmines and camouflaged enemies. when 9/11 happened, the brainwashed populace was led to believe that 19 middle-eastern terroristslearned how to fly commercial airliners (but never learned how to land them), crashed them into skyscrapers and this somehow brought down buildings demolition style, including a 50-story building the planes never hit. Plus, somehow, these same terrorists passports were found in pristine condition laying on the ground near the buildings. Someone must have thrown them out the plane window just before the big crash, so the fbi and cia could solve the case later. only people who are doped up on drugs in their water, food and medicine would fall hook-line-and-sinker for that false narrative, which makes no senseand contains no logic whatsoever. theres a reason that the mass media industrial complex of america always has a narrative prepared for mass-casualty events that happen, and thats because most of them are planned, stagedand carried out by government forces. This can mean that fbi and cia patsies are utilized (criminals trying to avoid more prison time), or paid stooges, or even agents themselves. Take a look at mass-shooting events, where the supposed shooter is always a young adult (white) male on psychiatric drugs (ssris) and uses an automatic weapon, but theres never a video of the event as it happened, even though every school, movie theatre and college campus has video cameras running 24/7/365. the past few years, weve all witnessed and experienced staged eventswhere the government immediately instructs the populace to take deadly medications, forfeit their guns, pay for more carnage and bow down to more police-state tyranny. Watch out for all those evil-doers out there looking to bring down america (communists in washington dc right now). so remember, if the news is blaming those pesky russians, or some invisible terrorists that hate capitalism, or simply telling everyone to stop using gasoline, take blood-clotting vaccines and start eating bugs for meals, the events that support these narratives are completely staged. Tune your apocalypse dial to preparedness.Newsfor updates on real news about surviving and thriving beyond what comes this way. This has been a public service announcement from natural health news. sources for this article include: censored.News naturalnews.Com top 7 strategies for spotting a staged event within the first 72 hours naturalnews.Comif border patrol nabs illegal immigrants, smuggler after spotting suv driving erraticalby beezer in forum illegal immigration news stories & reportsreplies: 1last post: 02-12-2023, 10:01 am - crisis actors used at sandy hook: infowars special report sandy hook staged eventby airbornesapper7 in forum other topics news and issuesreplies: 4last post: 12-09-2014, 06:21 pm - county issues video on spotting terrorismby johndoe2 08-24-2011, 11:28 pm - nevada pilots to fly spotting missions along az-mex borderby jean in forum illegal immigration news stories & reportsreplies: 0last post: 08-12-2006, 12:18 am
    ( Read More... | 11454 bytes more | comments? | Printer Friendly Page  Send this Story to a Friend )

     
    Regulating Tumor-Associated Macrophage Polarization by Cyclodextrin-Modified PLG
    Posted on Wednesday, April 17 @ 00:00:09 PDT (8 reads)
    College Guide [international journal of nanomedicine](international-journal-of-nanomedicine-journal) » [volume 19](international-journal-of-nanomedicine-archive5-v1792) regulating tumor-associated macrophage polarization by cyclodextrin-modified plga nanoparticles loaded with r848 for treating colon cancer authors [yuan h](author_profile.Php?Id=2011781), [gui h](author_profile.Php?Id=2013315), [chen s](author_profile.Php?Id=2013316), [zhu l](author_profile.Php?Id=2013327), [wang c](author_profile.Php?Id=2013318), [jing q](author_profile.Php?Id=2013322), [lv h](author_profile.Php?Id=2013323) , [wan q](author_profile.Php?Id=2013324), [wang s](author_profile.Php?Id=2024941), [zhou s](author_profile.Php?Id=2024942), [ren x](author_profile.Php?Id=2024943), [nie y](author_profile.Php?Id=792060), [li l](author_profile.Php?Id=2012841) received 8 december 2023 accepted for publication 10 april 2024 published 17 april 2024 volume 2024:19 pages 3589—3605 doi https://doi.Org/10.2147/ijn.S450205 review by [single anonymous peer review](peer-review-guidelines) peer reviewer comments 2 editor who approved publication: [dr yan shen](public_profile.Php?Id=156151) haohua yuan,1 huan gui,1 shuanghui chen,1 lan zhu,1 chenglv wang,1 qianyu jing,2 hang lv,1 quan wan,2 shuyi wang,1 shengwen zhou,1 xiaodong ren,1 yingjie nie,1,3 linzhao li1 1medical college, guizhou university, guizhou province, 550025, people’s republic of china; 2school of preclinical medicine of zunyi medical university, zunyi, guizhou province, 563000, people’s republic of china; 3nhc key laboratory of pulmonary immunological diseases, guizhou provincial people’s hospital, guiyang, guizhou province, 550002, people’s republic of china correspondence: yingjie nie; linzhao li, medical college of guizhou university, guiyang, guizhou province, 550025, people’s republic of china , tel +86-085188274013 ; +86-085188274016 , protection); [[email protected]](/cdn-cgi/l/email-protection) purpose: this study aimed to develop a novel and feasible modification strategy to improve the solubility and antitumor activity of resiquimod (r848) by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodextrin (2-hp-?-Cd). methods: r848-loaded plga nanoparticles modified with 2-hp-?-Cd (cd@r848@nps) were synthesized using an enhanced emulsification solvent-evaporation technique. The nanoparticles were then characterized in vitro by several methods, such as scanning electron microscopy (sem), differential scanning calorimetry (dsc), fourier transform infrared (ftir) spectroscopy, particle size analysis, and zeta potential analysis. Then, the nanoparticles were loaded with ir-780 dye and imaged using an in vivo imaging device to evaluate their biodistribution. Additionally, the antitumor efficacy and underlying mechanism of cd@r848@nps in combination with an anti-tnfr2 antibody were investigated using an mc-38 colon adenocarcinoma model in vivo. results: the average size of the cd@r848@nps was 376 ± 30 nm, and the surface charge was 21 ± 1 mv. Through this design, the targeting ability of 2-hp-?-Cd can be leveraged and r848 is delivered to tumor-supporting m2-like macrophages in an efficient and specific manner. Moreover, we used an anti-tnfr2 antibody to reduce the proportion of tregs. Compared with plain plga nanoparticles or r848, cd@r848@nps increased penetration in tumor tissues, dramatically reprogrammed m1-like macrophages, removed tumors and prolonged patient survival. conclusion: the new nanocapsule system is a promising strategy for targeting tumor, reprogramming tumor -associated macrophages, and enhancement immunotherapy. keywords: r848, 2-hp-?-Cd, anti-tnfr2, time, immunotherapy introduction cancer remains the leading cause of global mortality, and its incidence is projected to increase by 47% by 2040. [1](#cit0001), [2](#cit0002) over the past decade, the development of immunotherapies has revolutionized cancer treatment and garnered attention from clinicians and cancer patients worldwide. [3–5](#cit0003 cit0004 cit0005) cancer immunity is closely linked to the tumor immunosuppressive microenvironment (time), which is caused by tumor-associated macrophages (tams) and regulatory t cells (tregs). [6](#cit0006) notably, m2-like tams are prevalent among tumor-infiltrating immune cells, and their abundance often correlates with a poor prognosis. [7](#cit0007) treatments for tams can be divided into the following principal strategies: 1) directly eliminating or depleting tams, 2) inhibiting the recruitment of tams, and 3) reprogramming tumor-promoting m2 macrophages within tams into antitumor m1 macrophages. The first approach may lead to unforeseen side effects, and inhibiting tam recruitment could reduce therapeutic efficacy due to compensatory proliferation. [8](#cit0008) the third strategy can effectively reduce the number of m2 macrophages, increase the secretion of tnf-?, Il-6, and other cytokines, activate antitumor immune responses, reshape the immunosuppressive tumor microenvironment, and kill tumor cells. Numerous reports have demonstrated that tumors can be effectively treated by drug delivery systems that utilize a ‘turn enemies into friends’ approach, ushering in a new era of tumor treatment. [9–11](#cit0009 cit0010 cit0011) resiquimod (r848) can polarize tams from the m2-like phenotype to the m1-like phenotype. [12–14](#cit0012 cit0013 cit0014) however, the pharmacokinetics of r848 are suboptimal, particularly when the drug is administered in the peritoneal cavity; due to its relatively small size, r848 is rapidly diffused and leads to subsequent systemic toxicity. [15–17](#cit0015 cit0016 cit0017) conversely, the effectiveness of tlr7/8 agonists in cancer treatment may be improved by employing drug delivery strategies that enhance drug retention and targeted delivery while minimizing off-target toxicity. [17](#cit0017), [18](#cit0018) several nanomaterial-based immunomodulatory treatments can effectively target immunomodulatory agents, enhance immune responses at reduced doses, and lower systemic toxicity. [19](#cit0019) poly(d,l-lactic-co-glycolic acid) (plga), an fda-approved biodegradable polymer, stands out for its biocompatibility, safety, and controllable biodegradation rate. [3](#cit0003), [20](#cit0020) another seven-unit cyclic oligosaccharide compound, 2-hydroxypropyl-?-Cyclodextrin (2-hp-?-Cd), can notably increase water solubility when hydroxypropyl is incorporated. [21](#cit0021) moreover, 2-hp-?-Cd has a natural affinity to macrophages. [22](#cit0022) this compound naturally gravitates toward macrophages and can effectively solubilize numerous drugs that are usually insoluble in water. Recently, researchers have investigated the ability of r848-loaded cyclodextrin nanoparticles to enhance tam targeting in vivo. [23](#cit0023) furthermore, tumor necrosis factor receptor type ii (tnfr2) is the primary receptor of tnf in murine and human treg cells. [24](#cit0024), [25](#cit0025) accordingly, targeting tnfr2 can suppress treg activity. to address the limitations of tlr agonists, particularly their systemic toxic side effects in clinical settings, we developed a novel approach using plga nanocarriers to encapsulate the drug r848, denoted r848@nps. Additionally, we used 2-hp-?-Cd, denoted cd@r848@nps, to modify the plga carrier; this modification improved drug solubility and macrophage polarization while safeguarding the nanoparticles from aggregation and phagocytosis within the body ( [figure 1a](#f0001)). To investigate nanoparticle localization in vivo, we utilized in vivo imaging by incorporating the fluorescent dye ir-780 (ir-780-r848@nps) (a control group) or ir-780-cd@r848@nps. The morphology and state of the nanoparticles were investigated using transmission electron microscopy (tem), fourier transform infrared spectroscopy (ftir), and differential scanning calorimetry (dsc) techniques. [22](#cit0022) comprehensive in vitro and in vivo evaluations were conducted to determine the therapeutic potential of combining cd@r848@nps with anti-tnfr2 (a-t) in a cancer model ( [figure 1b](#f0001)). This approach might offer a straightforward and universally applicable strategy for delivering other hydrophobic cancer drugs on demand. materials and methods chemicals resiquimod (r848) was purchased from selleck (houston, tx, usa). Poly(d, l-lactic-co-glycolic acid) (plga) (la: ga = 50:50, 10–20 kda) and cell counting kit-8 (cck-8) were purchased from medchenexpress (monmouth junction, nj, usa). Poly(vinyl alcohol) (pva), the heptamethine indocyanine dye ir-780 iodide, and 2-hydroxypropyl-?-Cyclodextrin (2-hp-?-Cd) were obtained from sigma-aldrich co. (St louis, mo, usa). The anti-mouse tnfr2 (cd120b) antibody was purchased from bio x cell (west lebanon, nh). Hoechst 33,342 and lysotracker red dnd-99 were purchased from yeasen biotechnology (shanghai, china). All other reagents used were of the highest commercially available grade. animals if not otherwise indicated, animal experiments were performed using c57bl/6 mice (spf) acquired from spaefer biotechnology co, ltd. (Beijing, china). Breeding conditions are as follows: regular lighting, temperature of 20–25°c, constant humidity, air filtration, and free food and drinking water. Protocols for animal study were approved by the institutional animal care and use committee (iacuc) of guizhou university. cells cell cultures were conducted in the specified medium at a temperature of 37°c, in the presence of 5% co2. Regular monitoring was conducted to ensure absence of mycoplasma contamination. Raw 264.7 cells, utilized in investigations pertaining to the uptake of nanoparticles, were acquired from atcc and underwent cultivation in dulbecco’s modified eagles medium (abbreviated as dmem; manufactured by gibco). These cells were initially seeded at a concentration of 1×106 cells/ml, with 6-well plates serving as the experimental setup for qpcr analysis, while 12-well plates were utilized for image analysis. Subsequently, treatment involving the administration of 20 ng/ml of recombinant mouse il-4 (courtesy of peprotech) was carried out over a period of 48 hours in order to elicit an m2-like phenotype. preparation of different nanoparticles r848-loaded nanoparticles (r848@nps) were synthesized by employing the oil-in-water single-emulsion method as previously described. [26](#cit0026) the aqueous phase for this synthesis comprised a 1% w/v polyvinyl alcohol (pva) solution. In the organic phase, 40 mg of poly(d,l-lactic-co-glycolic acid) (plga) and 2 mg of r848 were dissolved in 1.0 ml of acetone/dichloromethane (3:2). The resultant mixture was sonicated for 10 minutes to create an emulsion. This organic solution was gradually introduced into 20 ml of the aqueous pva solution under ultrasonication (kunshan ultrasonic instrument co., Shanghai, china).) In an ice bath for 20 minutes, employing 3-second on and 3-second off pulses, resulting in the formation of an oil-in-water (o/w) emulsion. Unloaded nanoparticle cores (cd@nps) were fabricated using the same procedure without r848 in the organic phase. to synthesize cd@r848@nps, a solution containing a mixture of 2-hp-?-Cd (0.5% w/v in 1% pva in distilled water) was utilized as the dispersing phase during the emulsion solvent diffusion process. The subsequent steps were identical to those used to prepare r848@nps. Nanoparticles were collected and washed through three centrifugation cycles at 13,000 rpm for 10 minutes each. Fluorescent dye-labeled nanoparticles (ir-780-cd@r848@nps) were synthesized by substituting r848 with 2 mg of ir-780 dye, and all other conditions remained unchanged. The method of preparing ir-780-r848@nps was similar to that mentioned above, except that 2-hp-?-Cd was not present in the aqueous phase. characterization of different np formulations a malvern laser particle size analyzer (nano zs90, malvern instruments ltd., Uk) was used to comprehensively analyze the nanoparticle characteristics, including their particle size, zeta potential, and polydispersity index (pdi). Prior to the measurements, all the samples were resuspended in deionized water (ddh2o) at a concentration of 1 mg/ml and subjected to 20 minutes of sonication. [27](#cit0027), [28](#cit0028) to examine the nanoparticle morphology, a jem-2100 instrument (jeol ltd., Japan) was utilized for transmission electron microscopy (tem) analysis. loading capacity and entrapment efficiency to isolate the nanoparticles from any residual drug, the sample solution was washed repeatedly with water and centrifuged at 1000 rpm for 10 minutes. The supernatant was then transferred to a 3-kd ultrafiltration tube and subjected to a second centrifugation at 4 °c for 30 minutes at 9000 rpm to separate the nanoparticles from any small amount of the dissolved drug. The amount of r848 released was measured using uv–vis spectroscopy. The following equations were used to calculate the loading capacity (lc) and entrapment efficiency (ee): the passage provides information about the following variables: w0, w1, w2, and w3. W0 represents the total amount of r848, w1 represents the amount of r848 in the supernatant after low-speed centrifugation, w2 represents the amount of r848 in the 3-kd ultrafiltration filtrate, and w3 represents the weight of the nanoparticles. fourier transform infrared spectroscopy (ftir) for the analysis of r848 and the modified nanoparticle compositions, infrared spectroscopy experiments were conducted with an ftir spectrometer (nicolet 5 ftir, thermo scientific, waltham, ma, usa). The objective was to identify distinctive functional groups and elucidate the fabrication process of the nanoparticle system. To achieve this goal, the samples were blended with kbr powder, compacted into discs, and subsequently analyzed across a wavenumber range of 4000–400 cm?1. differential scanning calorimetry (dsc) the sample was heated in a controlled manner by utilizing a sealed aluminum pan with a heating rate of 5 ml/min. Dsc thermograms were generated using an automatic thermal analyzer (ta-20, shimadzu, tokyo, japan) with a temperature range of 30–300 °c. Notably, each sample contained a consistent quantity of 5 mg. in vitro release profiles to investigate the ph-dependent drug release kinetics, 20 mg of nanoparticles were dispersed in either 60 ml of release medium (pbs+0.1% w/v tween 80) with a ph of 7.4 or an environment simulating late endosomes/lysosomes with a ph of 5.0. [29](#cit0029), [30](#cit0030) the dispersion process was performed at 37 °c using a dialysis tube with a molecular weight cutoff of 3.5 kda. At specific time intervals, precisely 1 ml of the dialysate was sampled to measure the absorbance of r848 at a wavelength of 254 nm. Subsequently, an equivalent volume of fresh pbs was reintroduced into the system to maintain the overall volume. The amount of released r848 was determined using uv–visible spectroscopy. in vitro cytotoxicity to investigate the potential adverse effects of nanoparticles on mc38 cells, mc38 cells were cultured in rpmi 1640 medium supplemented with 10% fetal calf serum. A total of fifty thousand cells were then added to each well of 96-well plates. Next, the cells were exposed to the cd@nps and cd@r848@nps, and the concentration of r848 was varied between 5 and 80 µg/ml. After treatment, 10 ?L of cck-8 reagent (medchem express, monmouth junction, nj, usa) was added to each well, and the cells were incubated for 1 hour. Subsequently, the optical densities of the cells were determined at a wavelength of 450 nm using an imark microplate absorbance reader (bio-rad, usa). in vitro cellular uptake study to investigate the affinity of the modified nanoparticles for macrophages, we used ir-780 dye as a fluorescent label and loaded it into the nanoparticles. Raw264.7 cells were polarized into m2 macrophages using il-4 (10 ng/ml) for 24 h23. Subsequently, the cells were incubated with different ir-780-loaded nanoparticles (ir-780-r848@nps and ir-780-cd@r848@nps) for 6 hours. Following incubation, the cells were washed three times with pbs to prevent further uptake. Then, the cells were fixed with lysotracker red dnd-99 (yeasen, shanghai, china). After 15 minutes, the cells were washed three times with pbs again, and the nuclei were stained with hoechst for 10 minutes. The internalization process of the modified nanoparticles was observed using a fluorescence inverted microscope. in vitro macrophage repolarization assay a total of 1×105 raw 264.7 cells were seeded into each well of a six-well plate, and m2 macrophages were polarized in the same manner as previously described. The cells were then incubated with the nanoparticles at 37 °c for 24 hours, with a final concentration of 1 mg/ml for each nanoparticle. Afterward, both cells and cell supernatants were collected. The cells were stained with the markers cd11b, f4/80, cd86+, and cd206+, and the content was detected using flow cytometry (cytoflex, beckman coulter, usa). To analyze the expression of m1-related genes, rna was extracted from the harvested cells. Total rna (2 ?G) was reverse transcribed into complementary dna using hiscriptiii rt supermix for qpcr (vazyme, shanghai, china). The specific primers used in this process are shown in supplementary table 1. The annealing temperatures were further analyzed using bio-rad cfx maestro software. in vivo tumor targeting and biodistribution to further investigate the distribution of nanoparticles in mice and the affinity of nanoparticles for tumors, we incorporated the fluorescent dye ir-780 to track and locate the nanoparticles. Subsequently, we subcutaneously injected mc38 cells into balb/c mice to establish a tumor model. Subsequently, balb/c mice were intravenously injected with free ir-780 or ir-780-loaded nanoparticles (either ir-780-r848@np or ir-780-cd@r848@np) at a dose of 100 µg/kg. Fluorescence images were captured at various time points postinjection using the lumi iii system (usa). Moreover, the biological distribution of ir-780-cd@r848@nps was analyzed at different intervals post intravenous administration using the same system. Analysis of the fluorescence images was carried out using living imaging software. in vivo antitumor efficacy to further evaluate the antitumor effects of the nanoparticles in vivo, we conducted an experiment using female c57bl/6 mice. On day 0, we injected 1×106 mc38 cells into the right thigh of each mouse to establish a tumor model. The mice were categorized into the following groups: a control group that received pbs, a cd@np group, an anti-tnfr2 group (a-t), a cd@r848@np+anti-tnfr2 group (cd@r848@np+a-t), and an r848+anti-tnfr2 group (r848+a-t). All groups received the same r848 dose (1 mg/kg) via intravenous administration. treatment commenced when the tumor volume reached 200–300 mm³. On days 12, 16, and 20 after tumor inoculation, control (pbs), r848, cd@r848@nps, or cd@nps were intravenously administered to the mice. On days 13 and 18, the tumor-bearing mice were intraperitoneally injected with anti-tnfr2 (5 mg/kg) or pbs. Tumor growth was monitored with a caliper every two days, and tumor volume was calculated as (length × width × height)/2. After 18 days of treatment, one mouse from each group was randomly selected for imaging. Subsequently, the mice were euthanized, and their tissues (heart, liver, spleen, lungs, kidneys, and tumors) were surgically removed and preserved in formalin solution. The following day, the tissue samples were embedded in paraffin and sliced into thin sections measuring 4~5 ?M. These sections were then stained with hematoxylin/eosin (h&e) and mounted on poly-l-lysine-coated glass slides (safeline histopathology, centre, pune, india). The method of h&e staining is detailed described in the supplementary file (material and methods). analysis of antitumor immunity activation in vivo after the full treatment was complete, the mice were sacrificed on 10 days after the last dose (day 30), and the tumors and spleens were collected. Whole blood was collected and centrifuged at room temperature for 10 minutes at 3500 rpm. The levels of the cytokines il-12, il-6, and tnf-? In the serum were detected using elisa following the instructions provided by the reagent manufacturer. Additionally, flow cytometry was utilized to detect the polarization of macrophages in the tumor group. The cells were washed in facs buffer and stained with bv510-conjugated anti-mouse cd45 (1:500, biolegend, clone 30-f11, usa), fitc-conjugated anti-mouse cd11b (1:500, invitrogen, clone m1/70, usa), f4/80-conjugated anti-mouse pe (1:250, bd/pharmingen, clone bm8, usa), and cd86-conjugated anti-mouse bv421 (1:500, bd/pharmingen, clone gl1, usa) for 30 min at 4 °c. The stained cells were examined through a flow cytometer (bd facscelesta). Moreover, the infiltration of lymphocyte cells from the spleen and blood was assessed by fcm. The cells were stained with bv510-conjugated anti-mouse cd45 (1:100, biolegend, clone 30-f11, usa), bv605-conjugated anti-mouse cd3 (1:100, bd/horizon, clone 145–2c11, usa), and fitc-conjugated anti-mouse cd4 (1:250, biolegend, clone gk1.5, usa) antibodies. Bv421-conjugated anti-mouse cd8 (1:250, bd/pharmingen, clone 53e6.7, usa) was used. tumor tissue from c57bl/6 mice was cryosectioned at a thickness of 8 µm. The frozen sections were stained with primary antibodies for 60 minutes at room temperature and then incubated with secondary antibodies for 30 minutes. Afterward, the sections were counterstained with 4?,6-diamino-2-phenylindole (dapi). Images were acquired using a confocal microscope (nikon). The f4/80 (g1231) and cd206 (g1223) antibodies were obtained from servicebio technology co., Ltd. (Wuhan, china). the secretion of the cytokines il-6 and tnf-? In mouse tumor tissue sites was assessed through immunohistochemistry (ihc) and histopathology. Goat anti-rabbit tnf-? Igg (1:500; sigma, usa) and il-6 (1:500; sigma, usa) were used for the evaluation. rechallenge experiments in tumor-free mice to assess the potential immune memory generated by immune combination therapy with nanoparticles in mice, tumor-free mice in the cd@r848@np+anti-tnfr2 group (cd@r848@np+a-t) were monitored for 60 days after the last dose (day 80). On day 61, mc38 tumor cells were subcutaneously inoculated into the right thigh, while an equivalent amount of hepa1-6 tumor cells was inoculated on the opposite side (left side). Tumor size was systematically observed and recorded every two days. statistical analysis. if not explicitly stated, all data were reported as the mean ± standard deviation (sd). The mean differences were computed using a two-tailed student’s t-test or one-way anova, if deemed suitable, with the use of graphpad prism 8. The threshold for statistical significance was established at a significance level of p < 0.05. results characterization of cd@r848@nps the tem images depicted in [figure 2a](#f0002) illustrate the morphologies of various nanoparticles. At magnifications of ×10,000 and ×30,000, individual dispersions of nanoparticles without adhesion were observed. Remarkably, nanoparticles modified with 2-hp-?-Cd exhibited a distinct core-shell structure, accompanied by a substantial increase in particle size. as illustrated in [figure 2b](#f0002), the cd@r848@nps and cd@nps existed in an emulsified state. Over time, the cd@r848@nps remained stable in pbs at 4 °c. The zeta potential of the nanoparticle suspension was measured, revealing an approximate value of 21 ± 1 mv ( [figure 2c](#f0002)). The synthesized cd@r848@nps was 376 ± 30 nm in size ( [figure 2d](#f0002)), and the particle size distribution exhibited a relatively homogeneous pattern. The pdi of the nanoparticle solution was less than 0.2 for all of the samples. ftir was employed to determine the successful encapsulation of the drug and analyze the binding mode of r848 and the nanocarriers ( [figure 2e](#f0002)). The distinctive peaks observed at 1450 and 1646.4 cm?1 in the r848 spectrum correspond to the benzene ring and amide carbonyl, respectively. The spectral range of 2-hp-?-Cd, from 3600 to 3200 cm?1, primarily reflects the stretching vibration of the hydroxyl stretching vibrations. Notably, the characteristic peak of r848 in the cd@r848@np and cd@np spectra decreased, whereas the absorption peak resulting from the stretching vibration of amino and hydroxyl groups at 3409 cm–1 shifted to 3455 cm–1. This shift suggested that r848 binds to nanoparticles through hydrogen bonds and assumes an amorphous form. Furthermore, the presence of 2-hp-?-Cd in the plga nanoparticles did not alter the presence of r848. In the spectra of the cd@nps and cd@r848@nps, the characteristic absorption peak of r848 vanished, indicating that r848 was successfully encapsulated by the nanoparticles and that the unloaded drugs was removed through centrifugation. the melting peak of r848 was at approximately 193 °c ( [figure 2f](#f0002)). However, for cd@r848@nps, this melting peak was not observed; instead, a broad peak was observed, indicating that the crystallization process is relatively slow. This observation further confirmed that r848 was successfully encapsulated by the nanoparticles. the absorbance was measured using ultraviolet?Visible (uv?Vis) spectroscopy and plotted on a standard curve. Based on the formula and standard curve of r848 ( supplementary figure 1), the encapsulation efficiency and drug capacity of r848 in cd@r848@nps were determined to be 65.36 ± 3% and 3.11 ± 0.61%, respectively. the release of r848 from cd@r848@nps was studied by simulating an in vivo environment ( [figure 3a](#f0003)). After 72 h of incubation in pbs (ph 7.0) containing 0.1% w/v tween 80 at 37 °c, 58.85±0.67% of the r848 was released from the nanocapsules. In an esterase-rich environment, 70.16±1.19% of the r848 was released after 72 h. The rate of r848 release increased accordingly with decreasing ph, possibly because the amide bond between plga and the carboxyl group of r848 becomes more unstable in acidic solution. [31](#cit0031) to assess biocompatibility, the cytotoxicity of cd@nps, r848@nps, and cd@r848@nps to mc38 cells was evaluated using a cck8 assay ( [figure 3b](#f0003)). All the nanocapsules exhibited minimal cytotoxicity, indicating their potential as biocompatible nanomaterials and suitable drug delivery carriers. Moreover, the nanocapsules maintained excellent cytocompatibility, even at high concentrations. an in vitro analysis of hemolysis characteristics ( supplementary figure 2) revealed no red blood cell lysis in the supernatants of the cd@np and cd@r848@np groups when the r848 concentration was between 25 and 100 ?G/ml. The method of hemolysis test is detailed described in the supplementary file (material and methods). cd@r848@nps increased cellular uptake in vitro as depicted in [figure 4](#f0004), the cellular uptake levels of the 2-hp-?-Cd-modified nanoparticles were greater than those of the regular nanoparticles, possibly due to the natural affinity of 2-hp-?-Cd for macrophages. The fluorescence signals from the red and green channels clearly overlap, indicating that the internalized nps were transported through the lysosomal pathway upon cellular entry. Lysosome-mediated endocytosis is a crucial mechanism for the entry of nanomaterials into cells. Lysosomes are equipped with varying quantities of hydrolases, thereby facilitating the rapid destruction and degradation of internalized nps, which aligns with the findings of the in vitro release results. cd@r848@np induced macrophage reprogramming in vitro the effect of the nanoparticles on m2-like macrophage repolarization was investigated in vitro. Compared with free r848, r848@nps and cd@r848@nps significantly increased the number of m1 macrophages (f4/80+ and cd86+), suggesting that the m2 phenotype was successfully polarized toward the m1 phenotype ( [figure 5a–b](#f0005)). No significant differences were observed between r848@np and cd@r848@np, which suggested that both the nanomaterials promoted m1 macrophage polarization in vitro. to further investigate the polarization of macrophages by cd@r848@nps, we conducted quantitative real-time pcr (qpcr) to analyzed related genes ( [figure 5c](#f0005)). The results showed that cd@r848@nps significantly increased the expression of cd80, tnf-? And nos2 compared to m2 macrophages. Meanwhile, m2-type macrophage markers mrc1 and arg1 displayed the opposite tendency in cd@r848@nps group, which could be attributed to the enhanced polarization of macrophages induced by r848, and 2-hp-?-Cd could boost the effect. As showcased in [figure 5c](#f0005), r848 or r848@np similarly reduced mrc1 and arg1 expression, but the cd80 expression levels were decreased compared with cd@r848@nps. evaluation of the biological distribution of cd@r848@nps in vivo to evaluate the biodistribution patterns and therapeutic effectiveness of the nanodrugs in vivo, we constructed a hypodermic mouse model of mc38 cancer. The nanoparticles (cd@r848@nps or r848@nps) were loaded with a fluorescent dye (ir-780 dye) for biodistribution studies. The mice were intravenously administered the following formulations: ir-780 dye, nanocapsules loaded with ir-780 dye (ir-780-r848@nps), and 2-hp-?-Cd-modified nanocapsules containing ir-780 dye (ir-780-cd@r848@nps). Each mouse was administered 100 µg/kg of ir-780 dye. as illustrated in [figure 6a](#f0006), free ir-780 treatment caused little tumor retention, and fluorescence diminished after 24 h. Both types of nanoparticles labeled with fluorescence were disseminated rapidly throughout the mice, indicating that the nanocapsules exhibited passive biodistribution characteristics. Moreover, while the fluorescence intensity of ir-780-r848@nps decreased at 24h postinjection, that of ir-780-cd@r848@nps remained relatively elevated, and the fluorescence signal peaked at 48 h and then weakened slowly. This prolonged circulation effect exhibited by the modified nanoparticles was attributed to the presence of 2-hp-?-Cd on the plga surface. The abundant hydroxyl groups on the 2-hp-?-Cd surface augment the hydrophilicity of plga, bolstering its recognition by res. Consequently, the drug circulation time is prolonged and drug accumulation at cancerous sites is enhanced. [22](#cit0022), [32](#cit0032) ex vivo imaging of ir-780 fluorescence in the tumor and five important organs was performed when the ir-780-cd@r848@np group mice were sacrificed at different times ( [figure 6b](#f0006)), and quantitative analysis of the results was performed ( [figure 6c](#f0006)). Initially, during the early drug metabolism phase, fluorescence signals were localized predominantly in the liver and lungs before concentrating at the tumor site. Among the six organs analyzed, the liver and tumor were the major sites at which all particles accumulated. Remarkably, the tumor showed a bright fluorescence signal at 48 h, consistent with the in vivo biodistribution results. At 72 h postinjection, a notable concentration of nanoparticles was observed in the liver, likely attributable to their uptake by the reticuloendothelial system (res) and subsequent passive liver targeting. cd@r848@nps exhibit antitumor effects on mice with colon cancer following the series of in vitro screening experiments as above, cd@r848@np group exhibited better efficacy in tumor targeting and biodistribution compared with r848@np group, so the cd@r848@np was selected for the follow-up in vivo experiment to explore the antitumor efficacy. To evaluate the effect of cd@r848@nps on macrophage polarization and the tumor microenvironment in vivo, we subcutaneously implanted mc38 cancer cells into female c57bl/6 mice. The experimental design is illustrated in [figure 7a](#f0007). The treatment groups were pbs (n = 6), cd@nps (n = 6), anti-tnfr2 (a-t) (n = 6), cd@r848@nps+anti-tnfr2 (cd@r848@nps+a-t) (n = 6), and r848+anti-tnfr2 (r848+a-t) (n = 6). Representative images of mice from each group were captured on day 18 after the last dose. Representative images of mice from each group showed that tumors were eliminated in the cd@r848@nps+a-t group and were significantly reduced in the r848+a-t group compared with pbs group ( [figure 7b](#f0007)). Tumor volume analysis revealed no significant differences in tumor growth between the pbs and cd@np groups. However, significant inhibition of tumor growth was observed in the r848+a-t group. Notably, tumors in the r848+a-t group started to relapse at a later stage, possibly due to immune tolerance or systemic side effects of the drug. This result indicates that the nanodelivery system helps prevent systemic adverse reactions to the drug ( [figure 7c](#f0007)). Additionally, the body weights of mice did not change obviously, and survival in the cd@r848@nps+a-t was significantly extended ( [figure 7d](#f0007) and [e](#f0007)). to assess the biological safety of immune combination therapy, we performed euthanized and dissected the cd@r848@nps+a-t group on day 10 after the last dose injection (day 30). As shown in supplementary figure 3, staining of the main organs (heart, liver, spleen, lung, and kidney) revealed that the organs of the mice in the cd@r848@np+a-t group were structurally intact, the cells were tightly arranged, and no noticeable lesions were observed. These results demonstrate the absence of toxic side effects and confirms the safety of the nanoparticle immune combination therapy. antitumor immunity activation of cd@r848@nps in vivo the combination of cd@r848@nps and anti-tnfr2 (cd@r848@nps+a-t) had a substantial anticancer effect on the mc38 crc model. To elucidate the anticancer mechanism, the distribution of immune cells in the tumor, spleen and blood were analyzed via flow cytometry. compared with the other groups, the cd@r848@nps+a-t group exhibited a reduced number of cd4+ t cells and an increase in the number of cd8+ t cells ( [figure 8a–b](#f0008)) in spleen. Consistent with our observations in the spleen, the quantity of cd8+ t cells was increased in the peripheral blood of the cd@r848@nps+a-t group ( [figure 8c–d](#f0008)). as displayed in [figures 8e-f](#f0008), there was an increase in the number of f4/80+ cd11b macrophages and f4/80+ cd11b cd86+ cells in the cd@r848@nps+a-t group. This finding suggested that cd@r848@nps+a-t successfully polarized tams into antitumor macrophages. as tam polarization can increase the secretion of tnf-?, Interleukin-12 (il-12p70), and il-6, an immunohistochemical staining assay was conducted to determine the cytokine concentration. The cd@r848@np+a-t group exhibited considerably larger tnf-? And il-6-positive regions than the other groups, as evidenced by the immunohistochemical images ( [figure 8g](#f0008)). the expression of cd206 (m2 polarization marker) in tumor tissues was determined by immunofluorescence staining. In contrast to those in the control group, tumors derived from the cd@r848@nps+a-t group exhibited lower levels of cd206 expression ( [figure 8h](#f0008)). This finding suggested that tams were successfully reprogrammed to function as m1-like antitumor effector cells. to confirm that m2-like macrophage repolarization occurred, we collected blood and measured the secretion of il-12, il-6 and tnf-? Using an enzyme-linked immunosorbent assay (elisa). The results of the assay confirmed that higher levels of il-12, il-6, and tnf-? Were secreted by macrophages subjected to cd@r848@nps+a-t than by the control group ( [figure 8i](#f0008)). These cytokines can promote innate and adaptive immune responses. Cd@r848@nps can deliver cytokines regionally to t cells in tumor tissues, enhancing the cd8+ to regulatory t-cell ratio in tumor tissues and resulting in significantly improved antitumor efficacy against mc38 tumors. rechallenge experiments in tumor-free mice to ascertain whether cd@r848@np treatment elicited an “immune memory” response against mc38 tumors, cd@r848@np+a-t group tumor-free mice were monitored 60 days after the last dose (day 80). As liver cancer and colon cancer are common primary solid tumors with high morbidity, and the liver is a common site of colon cancer metastasis. And the mc38 and hepa1-6 cell lines are commonly used for liver and colon cancers, we selected these two cell lines for our study. Subsequently, the mc38 tumor cells were reintroduced into the rodents at the same site on the right side, whereas the hepa1-6 cancer cells were introduced to the contralateral side. The findings revealed that the cured mice developed hepa1-6 tumors but did not develop mc38 tumors ( [figure 9a–b](#f0009)). This finding suggested that the treated mice developed tumor-specific immune memory. discussion the objective of this study was to develop a novel nanoparticle system with high encapsulation efficiency to induce the transition of m2 macrophages to the m1 phenotype, and to enhance the immunotherapeutic efficacy of the system in mouse colon tumor models. To address issues of poor tumor penetration and low water solubility of conventional anticancer drugs, a nanodelivery system approach was utilized for combined immunotherapy. Plga nanocarriers modified with 2-hp-?-Cd were employed to encapsulate r848 (cd@r848@nps), enhancing water solubility and leveraging affinity for macrophages to modulate the tumor microenvironment. In vitro, cd@r848@nps demonstrated high biocompatibility and released over 70% of the drug in acidic conditions ( [figure 3](#f0003)). Nanoparticles modified with 2-hp-?-Cd (cd@r848@np) exhibited superior tumor localization and effectively induced m1 macrophage polarization, upregulating expression of key genes (cd80, tnf-?, Nos2) ( [figure 5](#f0005)). In vivo, cd@r848@np combined with anti-tnfr2 successfully eradicated subcutaneous colon cancer tumors and regulate the infiltration of cd8+t cells, the mice showed increased levels of il-12, tnf-? And il-6 in the plasma ( [figure 8i](#f0008)). Notably, free r848 treatment combined with anti-tnfr2 inhibited the growth of tumors at an early stage but promoted immune tolerance and tumor hyperprogression in vivo, indicating that cd@r848@nps+a-t achieved a better therapeutic effect. cancer thrives in an environment that suppresses the immune system. The effectiveness of immunotherapy is influenced by the immunosuppressive microenvironment of the tumor, which is primarily caused by m2 macrophages. [32](#cit0032) immunosuppressive cells prevalent in the tumor microenvironment primarily include tams, mdscs, and tregs. [33](#cit0033) tams exhibit a high degree of adaptability with opposing phenotypes and functions, which can either support tumor growth (eg, m2-like cells) or exhibit tumor-killing abilities (eg, m1-like cells). [34](#cit0034) han et al developed a plga nanodrug delivery system loaded with m2 macrophage-binding peptides that target m2, facilitating the specific transportation of baicalin, tumor antigens, and immune stimulators and augmenting antitumor immune responses. [35](#cit0035) this study focused on cyclodextrins (cds), a group of macrocyclic oligosaccharides connected by ?-1,4 glycosidic bonds. The cds consisted of ?-, ?-, And ?-Cds, which contained 6, 7, and 8 glucose units, respectively. Specifically, 2-hp-?-Cd was formed by substituting the second hydroxyl group in the ?-Cd structure with a hydroxypropyl group. [36](#cit0036) in contrast to cds, ?-Cds have demonstrated exceptional biocompatibility, distinct inclusion capacities, and potent functionalization capacities. Due to these attributes, cds and their derivatives are appealing options for developing innovative functional materials for biomedical applications. [37](#cit0037) consequently, plga was modified using ?-Cd to serve as a delivery vehicle for tumor immunotherapy. One of the main goals of cancer research is to develop novel therapies that can successfully slow the growth of tumors and prevent side effects, such as cachexia. Combination immunotherapy is a novel approach in this field. Anfray et al demonstrated that the poly(i:c)+r848 combination was more effective than any individual intervention, including r837. [38](#cit0038) additionally, researchers have discovered that compared to immunotherapy, targeted therapy is rapid and brief; thus, the two treatments might be combined to enhance one another’s advantages. When used in conjunction with cdnps, pd-1 antibodies can effectively reduce the growth of b16 tumors. [23](#cit0023) our preliminary studies demonstrated that combining hmgn1 and 3m-052 with an anti-tnfr2-stimulated dc vaccine can effectively enhance the activation of ctls by targeting treg cells and immature dcs. [39](#cit0039) this dual-targeted immunosuppression approach results in homologous immune memory and effective antitumor effects. [39](#cit0039) as a result, we employed an immunotherapy combination along with a nanodelivery method, and the outcomes met our expectations. Our study has certain limitations. For instance, other studies have indicated that active targeted nanomedicine delivery systems are superior to passive epr methods. [40](#cit0040) although more research is needed to determine the exact mechanism involved, some experts speculate that the mechanism involves the attraction of the dextran structure to macrophages. [41](#cit0041) consequently, enhancing the capacity of drug-targeted delivery in conjunction with immunological and oncological advancements would contribute to the development of safer and more efficient tumor immunotherapies. conclusion to achieve tumor clearance in colon cancer model, the current study proposed a novel immunotherapy strategy using a nanodelivery method. This strategy utilizes the inherent affinity of 2-hp-?-Cd for macrophages, enabling the targeted and efficient delivery of tlr agonist (r848) to time and reprogramming tumor-promoting m2-like macrophages toward a m1 phenotype with reduced systemic side effects in a specific manner. And in vitro experiments revealed that the nanoparticles were non-toxic, biocompatible and exhibited excellent macrophage targeting. Furthermore, cd@r848@np combined with anti-tnfr2 results in remarkable activation of antitumor effects and even confer antitumor immune memory, demonstrated as resistance to tumor rechallenge in treated mice. This study demonstrated the nanodelivery systems are important in tumor-targeting therapy which providing a valuable tool to improve outcomes in patients with solid tumors including colon cancer. These nanomaterials can also be used to encapsulate different hydrophobic medications, providing a versatile platform for the treatment of various diseases. abbreviations plga, poly (lactic-co-glycolic acid); crc, colorectal cancer; tem, transmission electron microscope; tlr, toll-like receptor; tam, tumor-associated macrophage; time, tumor immune microenvironment; tregs, cd4+foxp3+ regulatory t cells; a-t, anti-tnfr2; cd, ?-Cyclodextrin; r848, resiquimod; nps, bare plga nanoparticles; cd@nps, plga nanocapsules modified with 2-hp-?-Cd; r848@nps, r848 coated with plga nanoparticles; cd@r848@np, drug r848-loaded plga nanoparticles modified by 2-hp-?-Cd; cd@r848@np+a-t, cd@r848@np+anti-tnfr2; r848+a-t, r848+anti-tnfr2; ir-780-r848@nps, the drug r848 and ir-780 dye loaded with plga nanoparticles; ir-780-cd@r848@nps, the drug r848 and ir-780 dye loaded with plga nanoparticles modified with 2-hp-?-Cd. ethics approval all animal-related procedures were carried out based on an approved protocol from the institutional animal care and treatment committee (license number for laboratory animals: eae-gzu-2022-7088). Protocol for animals study were approved by institutional animal care committee of guizhou university. author contributions all authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. funding this work was supported by the national natural science foundation of china (82060308) and, national key laboratory of respiratory. Diseases (sklrd-op-202208), guizhou provincial science and technology projects (gpph-nsfc-2020-6; gpph-nsfc-2020-7; gcc [2022]037-1), guizhou provincial basic research program (natural science) (no. Qiankehe-basic-zk[2021]-general 405, qiankehe-basic-zk [2021]-general-556), qiankehe-basic-zk-[2024]-general-072), health commission of guizhou province (grant number: gzwkj2022-004), the 2018 talent research program of guizhou university (2018-53), guizhou university talent introduction research project (no. Guidarenjihezi (2020) number 76) and the funding from ministry of human resources and social security of the people’s republic of china. disclosure the authors report this work. sung h, ferlay j, siegel rl. Et al. Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca. 2021;71(3):209–249. Doi:10.3322/caac.21660 [2.](#Ref-cit0002) arbyn m, weiderpass e, bruni l, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet glob health. 2020;8(2):e191–e203. Doi:10.1016/s2214-109x(19)30482-6 [3.](#Ref-cit0003) dai z, yu x, hong j, liu x, sun j, sun x. Development of a novel csa-plga drug delivery system based on a glaucoma drainage device for the prevention of postoperative fibrosis. Mater sci eng c. 2016;66:206–214. Doi:10.1016/j.Msec.2016.04.077 [4.](#Ref-cit0004) vanamee És, faustman dl. Tnfr2: a novel target for cancer immunotherapy. Trends mol med. 2017;23(11):1037–1046. Doi:10.1016/j.Molmed.2017.09.007 [5.](#Ref-cit0005) binnewies m, roberts ew, kersten k, et al. Understanding the tumor immune microenvironment (time) for effective therapy. Nature med. 2018;24(5):541–550. Doi:10.1038/s41591-018-0014-x [6.](#Ref-cit0006) shamdani s, uzan g, naserian s. Tnf?-Tnfr2 signaling pathway in control of the neural stem/progenitor cell immunosuppressive effect: different experimental approaches to assess this hypothetical mechanism behind their immunological function. Stem cell res ther. 2020;11(1):307. Doi:10.1186/s13287-020-01816-2 [7.](#Ref-cit0007) da silva cg, camps mgm, tmwy l, et al. Effective chemoimmunotherapy by co-delivery of doxorubicin and immune adjuvants in biodegradable nanoparticles. Theranostics. 2019;9(22):6485–6500. Doi:10.7150/thno.34429 [8.](#Ref-cit0008) cassetta l, pollard jw. Targeting macrophages: therapeutic approaches in cancer. Nat rev drug discov. 2018;17(12):887–904. Doi:10.1038/nrd.2018.169 [9.](#Ref-cit0009) pan y, yu y, wang x, zhang t. Tumor-associated macrophages in tumor immunity. Front immunol. 2020;11:583084. Doi:10.3389/fimmu.2020.583084 [10.](#Ref-cit0010) rong l, zhang y, li w-s, su z, fadhil ji, zhang c. Iron chelated melanin-like nanoparticles for tumor-associated macrophage repolarization and cancer therapy. Biomaterials. 2019;225:119515. Doi:10.1016/j.Biomaterials.2019.119515 [11.](#Ref-cit0011) deng r-h, zou m-z, zheng d, et al. Nanoparticles from cuttlefish ink inhibit tumor growth by synergizing immunotherapy and photothermal therapy. Acs nano. 2019;13(8):8618–8629. Doi:10.1021/acsnano.9b02993 [12.](#Ref-cit0012) jiang m, liu j, yang d, et al. A tnfr2 antibody by countering immunosuppression cooperates with hmgn1 and r848 immune stimulants to inhibit murine colon cancer. Int immunopharmacol. 2021 101;108345 doi:10.1016/j.Intimp.2021.108345 [13.](#Ref-cit0013) smith m, garcía-martínez e, pitter mr, et al. Trial watch: toll-like receptor agonists in cancer immunotherapy. Oncoimmunology. 2018;7(12):e1526250. Doi:10.1080/2162402x.2018.1526250 [14.](#Ref-cit0014) dietsch gn, lu h, yang y, et al. Coordinated activation of toll-like receptor8 (tlr8) and nlrp3 by the tlr8 agonist, vtx-2337, ignites tumoricidal natural killer cell activity. Plos one. 2016;11(2):e0148764. Doi:10.1371/journal.Pone.0148764 [15.](#Ref-cit0015) rook ah, gelfand jm, wysocka m, et al. Topical resiquimod can induce disease regression, eradicate malignant t cells and enhance t cell effector functions in cutaneous t cell lymphoma. Blood. 2015. Doi:10.1182/blood-2015-02-630335 [16.](#Ref-cit0016) engel al, holt ge, lu h. The pharmacokinetics of toll-like receptor agonists and the impact on the immune system. Expert rev clin pharmacol. 2011;4(2):275–289. Doi:10.1586/ecp.11.5 [17.](#Ref-cit0017) varshney d, qiu sy, graf tp, mchugh kj. Employing drug delivery strategies to overcome challenges using tlr7/8 agonists for cancer immunotherapy. Aaps j. 2021;23(4):90. Doi:10.1208/s12248-021-00620-x [18.](#Ref-cit0018) lan h, zhang w, jin k, liu y, wang z. Modulating barriers of tumor microenvironment through nanocarrier systems for improved cancer immunotherapy: a review of current status and future perspective. Drug delivery. 2020;27(1):1248–1262. Doi:10.1080/10717544.2020.1809559 [19.](#Ref-cit0019) qodratnama r, serino lp, cox hc, qutachi o, white lj. Formulations for modulation of protein release from large-size plga microparticles for tissue engineering. Mater sci eng c. 2015;47:230–236. Doi:10.1016/j.Msec.2014.11.003 [20.](#Ref-cit0020) makadia hk, siegel sj. Poly lactic-co-glycolic acid (plga) as biodegradable controlled drug delivery carrier. Polymers. 2011;3(3):1377–1397. Doi:10.3390/polym3031377 [21.](#Ref-cit0021) santos ac, costa d, ferreira l, et al. Cyclodextrin-based delivery systems for in vivo-tested anticancer therapies. Drug delivery transl res. 2021;11(1):49–71. Doi:10.1007/s13346-020-00778-5 [22.](#Ref-cit0022) zheng k, huang z, huang j, et al. Effect of a 2-hp-?-Cyclodextrin formulation on the biological transport and delivery of chemotherapeutic plga nanoparticles. Drug des devel ther. 2021;15:2605–2618. Doi:10.2147/dddt.S314361 [23.](#Ref-cit0023) rodell cb, arlauckas sp, cuccarese mf, et al. Tlr7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat biomed eng. 2018;2(8):578–588. Doi:10.1038/s41551-018-0236-8 [24.](#Ref-cit0024) ren b, jiang b, hu r, et al. Hp-?-Cyclodextrin as an inhibitor of amyloid-? Aggregation and toxicity. Phys chem chem phys. 2016;18(30):20476–20485. Doi:10.1039/c6cp03582e [25.](#Ref-cit0025) facciabene a, motz gt, coukos g. T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer res. 2012;72(9):2162–2171. Doi:10.1158/0008-5472.Can-11-3687 [26.](#Ref-cit0026) fonseca c, simões s, gaspar r. Paclitaxel-loaded plga nanoparticles: preparation, physicochemical characterization and in vitro anti-tumoral activity. J control release. 2002;83(2):273–286. Doi:10.1016/s0168-3659(02)00212-2 [27.](#Ref-cit0027) perveen k, husain fm, qais fa, et al. Microwave-assisted rapid green synthesis of gold nanoparticles using seed extract of trachyspermum ammi: ros mediated biofilm inhibition and anticancer activity. Biomolecules. 2021;11(2):197. Doi:10.3390/biom11020197 [28.](#Ref-cit0028) mazumder s, dewangan ak, pavurala n. Enhanced dissolution of poorly soluble antiviral drugs from nanoparticles of cellulose acetate based solid dispersion matrices. Asian j. Pharm. Sci. 2017;12(6):532–541. Doi:10.1016/j.Ajps.2017.07.002 [29.](#Ref-cit0029) gong x, zheng y, he g, chen k, zeng x, chen z. Multifunctional nanoplatform based on star-shaped copolymer for liver cancer targeting therapy. Drug deliv. 2019;26(1):595–603. Doi:10.1080/10717544.2019.1625467 [30.](#Ref-cit0030) yao j, li y, sun x, dahmani fz, liu h, zhou j. Nanoparticle delivery and combination therapy of gambogic acid and all-trans retinoic acid. Int j nanomed. 2014;9:3313–3324. Doi:10.2147/ijn.S62793 [31.](#Ref-cit0031) ding w, guo l. Immobilized transferrin fe3o4@sio2 nanoparticle with high doxorubicin loading for dual-targeted tumor drug delivery. Int j nanomed. 2013;8:4631–4639. Doi:10.2147/ijn.S51745 [32.](#Ref-cit0032) xie x, li s, liu y, et al. Based on functional materials and plga for the florfenicol controlled release system and its antibacterial properties. React funct polym. 2022;178:105331. Doi:10.1016/j.Reactfunctpolym.2022.105331 [33.](#Ref-cit0033) pitt jm, marabelle a, eggermont a, soria jc, kroemer g, zitvogel l. Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Ann oncol. 2016;27(8):1482–1492. Doi:10.1093/annonc/mdw168 [34.](#Ref-cit0034) wang nx, von recum ha. Affinity-based drug delivery. Macromol biosci. 2011;11(3):321–332. Doi:10.1002/mabi.201000206 [35.](#Ref-cit0035) han s, wang w, wang s, et al. Tumor microenvironment remodeling and tumor therapy based on m2-like tumor associated macrophage-targeting nano-complexes. Theranostics. 2021;11(6):2892–2916. Doi:10.7150/thno.50928 [36.](#Ref-cit0036) hayashi t, crain b, corr m, et al. Intravesical toll-like receptor 7 agonist r-837: optimization of its formulation in an orthotopic mouse model of bladder cancer. International journal of urology: official journal of the japanese urological association. 2010;17(5):483–490. Doi:10.1111/j.1442-2042.2010.02503.X [37.](#Ref-cit0037) lipkowitz kb. Applications of computational chemistry to the study of cyclodextrins. Chem rev. 1998;98(5):1829–1874. Doi:10.1021/cr9700179 [38.](#Ref-cit0038) anfray c, mainini f, digifico e, et al. Intratumoral combination therapy with poly(i:c) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity. Journal for immunotherapy of cancer. 2021;9(9):e002408. Doi:10.1136/jitc-2021-002408 [39.](#Ref-cit0039) zhu l, zhang x, chen x, et al. Anti-tnfr2 enhanced the antitumor activity of a new hmgn1/3m-052 stimulated dendritic cell vaccine in a mouse model of colon cancer. Biochem biophys res commun 2023;653:106–114. Doi:10.1016/j.Bbrc.2023.02.039 [40.](#Ref-cit0040) combes f, meyer e, sanders nn. Immune cells as tumor drug delivery vehicles. J control release. 2020;327:70–87. Doi:10.1016/j.Jconrel.2020.07.043 [41.](#Ref-cit0041) pandit s, dutta d, nie s. Active transcytosis and new opportunities for cancer nanomedicine. Nature mater. 2020;19(5):478–480. Doi:10.1038/s41563-020-0672-1
    ( Read More... | 108932 bytes more | comments? | Printer Friendly Page  Send this Story to a Friend )

     
    Untouched
    Posted on Wednesday, April 17 @ 00:00:09 PDT (8 reads)
    College Guide | | mno edit summary | | no edit summary |(8 intermediate revisions by the same user not shown)| |line 27:||line 27:| | | [[lilah morgan|lilah]] sneaks into [[lindsey mcdonald|lindsey]]s office to rifle though his papers. Darla makes her presence known and reveals she has been using a drug called [[calynthia powder]] to keep angel asleep while she manipulates his dreams. | | [[lilah morgan|lilah]] sneaks into [[lindsey mcdonald|lindsey]]s office to rifle though his papers. Darla makes her presence known and reveals she has been using a drug called [[calynthia powder]] to keep angel asleep while she manipulates his dreams. |?|| | angel wakes to find [[cordelia chase|cordelia]] and [[wesley wyndam-pryce|wesley]] bickering about whether they should offer to pay [[charles gunn|gunn]]. As wesley and angel discuss the [[vampire]]s sleeping habits, cordelia suddenly gets [[visions]] that send angel out after a young woman from two [[human|men]] trying to attack her. As the men are about to make their move, she telekinetically slides a dumpster across the alleyway and uses it to crush them against the wall. |+|| | angel wakes to find [[cordelia chase|cordelia]] and [[wesley wyndam-pryce|wesley]] bickering about whether they should offer to pay [[charles gunn|gunn]]. As wesley and angel discuss the [[vampire]]s sleeping habits, cordelia suddenly gets [[visions]] that send angel out after a young woman from two [[human|men]] trying to attack her. As the men are about to make their move, she telekinetically slides a dumpster across the alleyway and uses it to crush them against the wall. |?|| | at the crime scene, angel pretends to be a detective to get information about the crime from [[landers|an officer]]. He wanders inside an old building and finds the woman from the alley. Panicked, she sends a rebar through angels chest |+|| | at the crime scene, angel pretends to be a detective to get information about the crime from [[landers|an officer]]. He wanders inside an old building and finds the woman from the alley. Panicked, she sends a rebar through angels chest she she him. To give much information and him to stay away the woman leaves, angel gives her his card. The woman returns to the apartment where she is staying: [[lilah morgans apartment|lilahs]]. | | gunn stops by [[angel investigations]] to offer his help, and angel sends him out to find information on the men bethany killed. | | gunn stops by [[angel investigations]] to offer his help, and angel sends him out to find information on the men bethany killed. |?|| | as bethany drifts off to sleep, she dreams of her abusive childhood and sends a bedside lamp flying. It hits lilah, who had been watching her fitful sleep |+|| | as bethany drifts off to sleep, she dreams of her abusive childhood and sends a bedside lamp flying. It hits lilah, who had been watching her fitful sleep , the . Bethany seeks angels help at the [[hyperion hotel]], and they discuss how she cannot control her . |?|| | at [[wolfram & hart los angeles branch|wolfram & hart]], holland and lilah |+|| | at [[wolfram & hart los angeles branch|wolfram & hart]], holland and lilah bethany lilah and been grooming to become an assassin for wolfram & hart responsible for the alley attack as a way of testing her. Holland lilah could damage their other projects. |?||+|| | bethany, wesley realizes her powers have arisen from having been sexually abused by her father. He then mentions her father, her to lose control and hurl he and angel through the air. |?|| | that night, bethany finds angel in his bed and offers to have sex with him; the abuse she has suffered has led her to believe that she is just an object for mens amusement. Angel declines |+|| | that night, bethany finds angel in his bed and offers to have sex with him; the abuse she has suffered has led her to believe that she is just an object for mens amusement. Angel declines and sends her back to her own bed. Darlas attempts to manipulate angels dream. When holland hears of this, he orders lilah to get bethany away from angel. |?|| | after angel helps bethany |+|| | after angel helps bethany to control her , he meets gunn at one of the attackers apartment. Brings up the idea gunn gunn is now officially part of angel investigations. They find evidence that the attempted rapist works for wolfram & hart. |?|| | cordelia talks to bethany over coffee, trying to convince her that she is no longer just a victim |+|| | cordelia talks to bethany over coffee, trying to convince her that she is no longer just a victim has great power and can choose how to use it her choices so far have not been . Wolfram & harts men arrive and kidnap bethany. Angel and gunn go after , . |?|| | wolfram & hart decide to increase the pressure and they send bethanys father to intercept her. This causes her to panic, and she lets out a blast of telekinetic power. All of the windows on the hotels top floor explode |+|| | wolfram & hart decide to increase the pressure and they send bethanys father to intercept her. This causes her to panic, and she lets out a blast of telekinetic power. All of the windows on the hotels top floor explode and both angel and cordelia are thrown backwards. Bethany hurls her father out a window, just before he hits the ground , . |?|| | later, bethany packs up her things in the apartment while lilah and angel have a chat at the door. Angel comments that lilah needs to find someone elses mind to play with. As he leaves with bethany, lilah mutters that they already have. |+|| | later, bethany packs up her things in the apartment while lilah and angel have a chat at the door. Angel comments that lilah needs to find someone elses mind to play with. As he leaves with bethany, lilah mutters that they already have. | | ==continuity== | | ==continuity== latest revision as of 02:14, 17 april 2024 untouched is the fourth episode of the [second season](/wiki/angel_season_2) of [angel](/wiki/angel_(series)) and the twenty-sixth episode in the series. Written by [mere smith](/wiki/mere_smith) and directed by [joss whedon](/wiki/joss_whedon), it was originally broadcast on october 17, [2000](/wiki/2000), on [the wb](/wiki/the_wb) network. synopsis sleep tight — [angel](/wiki/angel) unknowingly crosses paths with [wolfram & hart](/wiki/wolfram_%26_hart) when he comes to the aid of a young woman, [bethany](/wiki/bethany), who possesses [telekinetic](/wiki/telekinesis) powers far beyond her control, a situation angel has had to contend with in his own life. Meanwhile, angel is somewhat off his game due to the fact that he has been sleeping weird, but has no idea his fitful nights are the result of nocturnal visits by [darla](/wiki/darla). [[1]](#cite_note-1) summary [lilah](/wiki/lilah_morgan) sneaks into [lindsey](/wiki/lindsey_mcdonald)s office to rifle though his papers. Darla makes her presence known and reveals she has been using a drug called [calynthia powder](/wiki/calynthia_powder) to keep angel asleep while she manipulates his dreams. angel wakes to find [cordelia](/wiki/cordelia_chase) and [wesley](/wiki/wesley_wyndam-pryce) bickering about whether they should offer to pay [gunn](/wiki/charles_gunn) for helping them fight demons. As wesley and angel discuss the [vampire](/wiki/vampire)s sleeping habits, cordelia suddenly gets [visions](/wiki/visions) that send angel out after a young woman from two [men](/wiki/human) trying to attack her. As the men are about to make their move, she telekinetically slides a dumpster across the alleyway and uses it to crush them against the wall. at the crime scene, angel pretends to be a detective to get information about the crime from [an officer](/wiki/landers). He wanders inside an old building and finds the woman from the alley. Panicked, she sends a rebar through angels chest. Realizing she did not kill him, she relaxes enough to let him talk to her. She is unwilling to give much information and warns him to stay away. Before the woman leaves, angel gives her his card. The woman returns to the apartment where she is staying: [lilahs](/wiki/lilah_morgan%27s_apartment). gunn stops by [angel investigations](/wiki/angel_investigations) to offer his help, and angel sends him out to find information on the men bethany killed. as bethany drifts off to sleep, she dreams of her abusive childhood and sends a bedside lamp flying. It hits lilah, who had been watching her fitful sleep. Lilah pleads with her to stay, but bethany flees the apartment realizing she hurt another person with her powers. Bethany seeks angels help at the [hyperion hotel](/wiki/hyperion_hotel), and they discuss how she cannot control her telekinesis. at [wolfram & hart](/wiki/wolfram_%26_hart_los_angeles_branch), holland and lilah discuss bethany - she is lilahs discovery and they have been grooming her to become an assassin for wolfram & hart. It is revealed the firm is responsible for the alley attack as a way of testing her telekinetic abilities. Holland tells lilah that her failure in grooming bethany could damage their other projects. after cordelia warns wesley about bethanys strange behavior, wesley realizes her powers have arisen from having been sexually abused by her father. He then approaches bethany and offhandedly mentions her father, thus causing her to lose control and hurl he and angel through the air. that night, bethany finds angel in his bed and offers to have sex with him; the abuse she has suffered has led her to believe that she is just an object for mens amusement. Angel declines and assures bethany all men arent like that. He then sends her back to her own bed. This conversation is shown to have interrupted darlas attempts to manipulate angels dream as she hides in the dark corner and watches angel send bethany away. When holland hears of this, he orders lilah to get bethany away from angel. after angel helps bethany attempt to control her powers, he meets gunn at one of the attackers apartment. Angel brings up the idea of paying gunn for his services and he readily agrees. Gunn is now officially part of angel investigations. They eventually find evidence that the attempted rapist works for wolfram & hart. cordelia talks to bethany over coffee, trying to convince her that she is no longer just a victim. She has great power and can choose how to use it - although her choices so far have not been wise. Cordelia warns her that sex with angel is off limits and that he is old fashioned with a different mindset than most men. Suddenly wolfram & harts men arrive and kidnap bethany. Angel and gunn go after them, eventually saving her. wolfram & hart decide to increase the pressure and they send bethanys father to intercept her. This causes her to panic, and she lets out a blast of telekinetic power. All of the windows on the hotels top floor explode and both angel and cordelia are thrown backwards. Bethany hurls her father out a window, stopping him from impending death just before he hits the ground. Bethany chooses not to kill her father, as she has remembered angel and cordelias teachings. later, bethany packs up her things in the apartment while lilah and angel have a chat at the door. Bethany accuses lilah of trying to kill her and tells her she no longer trusts her. Angel comments that lilah needs to find someone elses mind to play with. As he leaves with bethany, lilah mutters that they already have. continuity - cordelia argues she was top 10% of her class; while in high school, she was accepted in prestigious colleges ( [choices](/wiki/choices)) and had an impressive sat score ( [lovers walk](/wiki/lovers_walk)). - cordelia refers to the [buffy the vampire slayer](/wiki/buffy_the_vampire_slayer)episode lovers walk when she mentions being impaled by a rebar. - cordelia claims: you cant fire me. Angel will fire all of his employees, including her, in the episode [reunion](/wiki/reunion). - gunn has a new axe, which he will use often in battles until its destruction in [apocalypse, nowish](/wiki/apocalypse,_nowish). - gunn asks if cordelia is still saving his life, a mission she first declared in [first impressions](/wiki/first_impressions). - angel says bethany wouldnt like him when hes happy, referring to his curse that makes him [soulless](/wiki/soul)and evil if he experience happiness ( [innocence](/wiki/innocence)). appearances individuals [angel](/wiki/angel) [cordelia chase](/wiki/cordelia_chase) [mr. Chaulk](/wiki/mr._chaulk) [bethany chaulk](/wiki/bethany_chaulk) [darla](/wiki/darla) [charles gunn](/wiki/charles_gunn) [landers](/wiki/landers) [lindsey mcdonald](/wiki/lindsey_mcdonald)(only mentioned) [holland manners](/wiki/holland_manners) [lilah morgan](/wiki/lilah_morgan) [wesley wyndam-pryce](/wiki/wesley_wyndam-pryce) [unidentified aggressor](/wiki/unidentified_aggressor) [unidentified detective](/wiki/unidentified_detective) organizations and titles species locations - romania (only in visions) - united states [los angeles](/wiki/los_angeles) [hyperion hotel](/wiki/hyperion_hotel) [lilah morgans apartment](/wiki/lilah_morgan%27s_apartment) [pearson arms apartments](/wiki/pearson_arms_apartments)(only mentioned) [pearson arms apartment 212](/wiki/pearson_arms_apartment_212)(only mentioned) [wesley wyndam-pryces apartment](/wiki/wesley_wyndam-pryce%27s_apartment)(only mentioned) [wolfram & hart los angeles branch](/wiki/wolfram_%26_hart_los_angeles_branch) - - ohio (only mentioned) [sunnydale](/wiki/sunnydale)(only mentioned) - objects death count - two attackers, crushed by bethany with a dumpster. behind the scenes production - this is the first episode to be written by mere smith, who would remain as one of the shows main writers until the end of the fourth season. - this is the only episode in the [buffyverse](/wiki/buffyverse)in which joss whedon directed but didnt also write. broadcast - untouched had an audience of 3.4 million households upon its original airing. [[2]](#cite_note-2) pop culture references - cordelia complains about wesleys avarice by calling him ebenezer, referring to the protagonist of the novella a christmas carol. - angel says: you wouldnt like me when im happy. This is a spoof of the popular phrase you wouldnt like me when im angry by david banner from the incredible hulk)1978 television series. - angel compares the officers uniform to of cub scout, a program associated with scouting for young children. - the officer quotes: oh, no, mr. Bill! mr. Billis a clay figurine from saturday night livesketches from the late 70s that generally ended with the character being crushed or dismembered while squealing: oh no! goofs - when bethany is confronting her father, we initially see angel lying on the ground behind her father, as seen over bethanys shoulder. In the next two shots from this angle, angel is standing up, clearly pinned against the wall. Moments later, however, angel is lying on the ground again, then stands up and is pinned against the wall by bethanys power. music - opus music library — at the fairground [robert j. Kral](/wiki/robert_j._kral)— untouched/darlas fire - robert j. Kral — original score international titles - czech: nedot?Ená (untouched) - finnish: viaton tyttörukka (innocent girl) - french: intouchable (untouchable) - german: außer kontrolle (out of control) - hungarian: az érinthetetlen (the untouchable) - italy: non toccarmi! (Dont touch me!) - portuguese (brazil): intacto (intact) - russian: ????????????? (Untouchable) - spanish (latin america): intacto (intact) - spanish (spain): intacto (intact) - turkish: dokunulmam?? (Untouched) quotes |wesley: thats so typical of your kind.| |cordelia: well, at least im not a sheep like you.| |wesley: i am not a sheep!| |cordelia: you are such a sheep! Youve never had a single opinion you didnt read in a book.| |wesley: at least ive opened a book.| |cordelia: oh, dont even try with the snooty, woolly boy. I was top 10% of my class.| |wesley: what class? Advanced bosoms?| |cordelia: oh!| |cordelia: [gunns] been doing for us. He should pull in a check.| |angel: ill think about asking him, all right?| |cordelia: no think. Pay. Thats an order.| |angel: hey! How about we pretend that you work for me.| |cordelia: you are unpleasant when you—| |angel: then why dont you pretend that you dont.| |cordelia: you cant fire me. Im vision-girl.| |cordelia: i cant get this bandage to— stop moving.| |angel: im not.| |cordelia: well, then stop breathing.| |angel: i dont breathe.| |cordelia: then stop flexing your manly boob muscles or whatever.| |angel: what do we know about telekinesis?| |wesley: ah, yes. The power of moving things with ones mind... Thats pretty much it.| |bethany: you can do stuff to me, and... You know... Well have some fun.| |angel: thats not gonna happen, bethany.| |bethany: what, like im some frightened little mouse? Ive done stuff. I can make you happy.| |angel: you wouldnt like me when im happy.| references [?](#Cite_ref-1) season two.City of angel. Archived from the original on june 6, 2011. [?](#Cite_ref-2) nielsen ratings for angels second season.Nielsen ratings for buffy the vampire slayer, angel, & firefly. Archived from the originalon july 19, 2008.
    ( Read More... | 34374 bytes more | comments? | Printer Friendly Page  Send this Story to a Friend )

     
    Where is Ecuador going after international “embarrassment”? – DW – 04/16/2024
    Posted on Wednesday, April 17 @ 00:00:09 PDT (31 reads)
    College Guide Ecuador is experiencing a turbulent legislature. A series of sudden events since ecuadorian president daniel noboa began his term last november have put the latin american country in the spotlight. a national state of emergency was added in january following a series of violence in prisons, followed by an attack on the mexican embassy in quito in early april to oust former vice president jorge glass. ngoba has been forced to be in office for half a year – as the legislature will only last sixteen months – which has so far not helped curb the grave situation of insecurity, drug trafficking and violence in the country. given this scenario, ecuadorians are going to vote on april 21 in a referendum and popular consultation on other questions of an economic nature in addition to the security questions proposed by noboa. experts tell dw that, if he is victorious in the consultations, noboa could argue that he needs more time in power to continue necessary reforms in the fight against organized crime. “his party can take advantage of this for the next presidential elections, in which he will run again,” gledis gonzalez, latin america member of the international crisis group (icg), told dw. a referendum to validate “on behalf of citizens, noboa hopes to improve the situation of insecurity, so everything he does is politically in that direction,” guillaume long, lead researcher at the center for economic policy research (cepr), told dw. ” Abbreviation in english), in london. “they have proposed a popular consultation, a referendum, which i would call ‘punitive populism,” says long, referring to the questions submitted for this sunday. ecuadorians will have to answer eleven questions, which relate to proposals including allowing the support of the armed forces in the functions of the national police, arms control, increasing penalties for serious crimes or extradition, according to information published by the national electoral council ( cne) by country. “it appeals to the idea that increasing sentences will deter crime, when the problem is not the number of years in prison but the impunity for crimes,” said pablo ospina, a professor in the area of ??Social and global studies at simon bolivar andean university. he added, “the questions of consultation were not designed to address fundamental solutions to insecurity, but to be politically strengthened by the impact of the coup.” “embarrassment” from the outside. The referendum comes days after the international “embarrassment” over the raid on the mexican embassy in quito, and despite the fact that, internally, noboa has also improved its reputation, underlined analysts consulted by dw. Has gone. “this demonstration represents exactly the kind of unrestricted fight against crime that the people who voted for him expected,” gladys gonzalez told dw. He further added, “the government was experiencing a progressive decline in its popularity and, perhaps, this was a strategy to improve its reputation, which has been well received in areas with anti-corista sentiments.” similarly, pablo ospina believes that this action marks the end of “his political alliance with chorismo”, as noboa’s party – national democratic action (adn) – had a parliamentary alliance with the civil revolution movement. Its leader, rafael correa, was a close friend of george glass. ospina says, “the occupation of the mexican embassy, ??In addition to creating a major embarrassment, marks a clear turn towards motivating the anti-corista vote.” for mario pazmino, international intelligence and security advisor for latin america and europe at the security college us, noboa’s image on the national level has been strengthened after the attack. “The country was tired of the permanent violation of its integrity and respect for ecuador’s democracy,” he told dw. ecuadorians go to the polls to answer eleven questions in a referendum and popular consultation, ranging from gun control to increasing penalties for serious crimes. Image: santiago arcos/reuters “trick” question the referendum consists of two questions that point, on the one hand, to ecuador’s return to international arbitration as a method of resolving investment disputes and, on the other hand, to allowing hourly work. “neither one nor the other has anything to do with security,” long says. But given that he had a very good chance of winning, noboa introduced them. It’s hard to do because they are complex issues. And there are many interests.” for the expert, the resumption of international arbitration – prohibited in ecuador by article 422 of its constitution – is “regrettable” and is caused “not only by ignorance”, but also by the specific interests of business groups “including the noboa group”. It also happens due to. He explains that all this belongs to the president himself. counseling will not solve insecurities some experts describe noboa’s security management as “positive”, although new proposals are necessary. As for mario pazmiño, “there is a need to restructure the prison system, the intelligence system and the judicial system, because a large part of the judges work for organized crime,” he assures dw. according to the ecuadorian organized crime observatory (oeco) with a rate of 47.25 violent deaths per 100,000 inhabitants, ecuador closed 2023 with more than 8,004 intentional homicides. This places it as the most violent country in latin america and one of the most violent countries in the world. “crime has not been brought under control and it may take decades,” gonzalo ordóñez, a researcher in the communications area of ??Simón bolívar andean university, tells dw. However, from the point of view of the next elections, the referendum is extremely valuable,” he says, despite all the criticism. (rml) source link
    ( Read More... | 11814 bytes more | comments? | Printer Friendly Page  Send this Story to a Friend )

     
    Smartphone messages strongly reduce blood pressure through spirituality
    Posted on Wednesday, April 17 @ 00:00:09 PDT (8 reads)
    College Guide In recent research presented at the american college of cardiology’s annual scientific session, a new study has found that daily messages designed to boost spirituality can significantly lower blood pressure in people with hypertension, commonly known as high blood pressure. this condition affects almost half of all adults in the u.S., And despite the availability of medications and lifestyle changes that can manage it, it remains poorly controlled in about 75% of those affected. the study, led by maria emília teixeira, md, from the medical school of the federal university of goiás in brazil, investigated whether spirituality—defined as the moral and personal values that guide our lives and relationships—could help manage blood pressure and enhance heart health. this approach to health care is grounded in previous studies that have linked spirituality-based interventions like meditation and positive social interactions with cardiovascular benefits. however, most of those studies were observational, making it difficult to definitively say they improve health outcomes. dr. Teixeira and her team embarked on this investigation by enrolling 100 patients with hypertension at a medical center in brazil. these participants were randomly divided into two groups: one received a daily spiritual intervention via smartphone messages, and the other did not receive any intervention. the intervention consisted of short messages and videos sent through whatsapp. These messages encouraged participants to reflect on themes such as optimism, gratitude, and forgiveness, emphasizing personal growth rather than religious belief. the researchers tracked which participants opened the messages and followed the activities suggested, like writing a message of gratitude, though they didn’t measure how engaged participants were with the content. the health of the participants was rigorously monitored over the 12-week study period. At the beginning and end of the study, all participants underwent a comprehensive health evaluation that assessed lifestyle habits, medication use, blood pressure, and flow-mediated dilation—a technique that measures the health of blood vessels. the findings were noteworthy. Participants who engaged with the spirituality messages saw their systolic blood pressure drop by an average of 7 mmhg. they also showed significant improvements in flow-mediated dilation, improving by 4.5%, which indicates better blood vessel health. In contrast, those in the control group, who did not receive the messages, experienced a decline in their blood vessel health by 3%. dr. Teixeira highlighted the significance of these results, stating that the reduction in blood pressure could potentially increase lifespan and reduce the risk of heart attacks, kidney disease, strokes, and other serious health issues later in life. this drop in blood pressure is notable, as it surpasses reductions seen with other non-drug interventions and may even be more effective than some medications. the simplicity and low cost of the intervention suggest that it could be easily implemented on a wider scale, although it does require participants to have access to a smartphone or similar device, which could limit its use in less connected populations. the researchers are optimistic about the potential to expand this approach to include other positive psychological factors, such as compassion and life satisfaction. despite the promising results, the researchers acknowledged that the study’s small size could be a limitation and that larger studies would be necessary to confirm these findings. however, the initial results are encouraging and suggest that integrating spirituality into daily health care routines via technology could be a beneficial tool in managing hypertension and improving overall cardiovascular health. if you care about high blood pressure, please read studies that early time-restricted eating could help improve blood pressure, and natural coconut sugar could help reduce blood pressure and artery stiffness . for more information about blood pressure, please see recent studies about added sugar in your diet linked to higher blood pressure , and results showing vitamin d could improve blood pressure in people with diabetes . copyright © 2024 knowridge science report . All rights reserved.
    ( Read More... | 8694 bytes more | comments? | Printer Friendly Page  Send this Story to a Friend )

     
    La Jolla News Nuggets: Free-speech pads, Scientist of the Year, Tour dElegance p
    Posted on Wednesday, April 17 @ 00:00:09 PDT (8 reads)
    College Guide La jolla news nuggets: free-speech pads, scientist of the year, tour d’elegance parade, pirch layoffs, more news and events briefs ‘expressive activity’ zones relocated in scripps park controversial “expressive activity” areas in la jolla are being shifted to accommodate views to the ocean following comments from community members. The 4-by-8-foot pads were placed in scripps park to give “first amendment vendors” (those operating under first amendment free-speech protections) a place to legally operate. By limiting the places where they can be, the intent is to reduce the number of the vendors in local parks. Vicky joes, representing the office of san diego city councilman joe lacava, whose district 1 includes la jolla, said la jollans had alerted the office that the pads had the potential to block view corridors that are outlined in the la jolla community plan. “That is not something that was on my radar, so i thank everyone for bringing that to our attention,” joes said. The pads were removed and new ones were installed soon after. La jolla professor named scientist of the year terry sejnowski, a scientist at the salk institute for biological studies in la jolla, has been named the 2024 achievement rewards for college scientists foundation’s scientist of the year. Sejnowski, considered one of the world’s foremost computer scientists and computational neuroscientists, has done work on neural networks that has laid the foundation for machine learning and artificial intelligence. He is the head of the salk institute’s computational neurobiology laboratory and holder of the frances crick chair and a distinguished professorship at uc san diego’s school of biological sciences, where he is co-director of the institute for neural computation. Arcs san diego will honor sejnowski and 50 arcs scholars on saturday, april 27, at the conrad prebys performing arts center in la jolla. All funds raised at the event will support future arcs scholars. Learn more at [san-diego.Arcsfoundation.Org](https://san-diego.Arcsfoundation.Org). Tour d’elegance to parade through la jolla shores as part of this weekend’s la jolla concours d’elegance car show, the tour d’elegance will parade 100 cars along avenida de la playa beginning at 11:30 a.M. Saturday, april 20. Residents are invited to line the street to view the cars, which will be going through the shores for the first time. The la jolla tour d’elegance provides car enthusiasts the opportunity to share their love of cars and connect with fellow aficionados. The three-day la jolla concours d’elegance festivities kick off friday, april 19, with a vip party and also will include “porsches on prospect” on saturday and the traditional car show in scripps park on sunday, april 21. Learn more at [lajollaconcours.Com](https://lajollaconcours.Com/). Pirch issues layoff notices to 23 employees of utc store more than 20 employees at the westfield utc location of luxury kitchen and bath retailer pirch were given layoff notices amid abrupt store closures and lawsuits. Pirch is the subject of more than a dozen civil suits filed in recent weeks by its landlords, customers and at least one merchant, alleging the company owes more than $5 million for unpaid rent and inventory. The san diego county-based company halted operations march 20. Two landlords claimed in recent court filings that pirch owed almost $850,000 in back rent — at its oceanside distribution center and the 23,747-square-foot utc showroom. The complaint about the utc space says pirch had failed to keep up on rent of more than $96,000 a month and owed more than $648,000. This month, the company issued 40 layoff notices, including 23 for the utc location. — The san diego union tribune diabetes drug being studied so positive effects can be isolated a diabetes drug considered to be “outdated” due to its side effects is being studied again to determine whether its positive effects can be isolated. Thiazolidinediones, or tzds, are a class of drug that can be used to treat type 2 diabetes by reversing insulin resistance, one of the main hallmarks of the disease. Tzds were popular in the 1990s and early 2000s but have fallen out of use among physicians in recent decades because they were discovered to cause unwanted side effects, including weight gain and excess fluid accumulation in body tissues. Now, researchers at the uc san diego school of medicine are exploring how to isolate the drugs’ positive effects, which could help yield new treatments that don’t come with the old side effects. In a new [ study](https://u7061146.Ct.Sendgrid.Net/ls/click?Upn=u001.Gqh-2baxuzlo7xkiusly0rc0c9cga68yvkwludtt3oqwr5vl11i2c8mvpnb1ewgvrtpdhizrzz4bjljqvtwamsqa-3d-3dqriq_ke788xezlrivzaw8e8t8nyjo8n33v52wqm16np2xei93ktguh10ehz7h8-2flrctvtut68qtdcicdzqlb2nubdgurv-2fonvpqhb2gbrxsytgjjatp2fjozptzstkvgindpx87xbrf0fnutyndzp6os4zxxg00mmxuwsar4eftapyb-2brijltq-2frp0snyjxhtnmcuyk7stngblcc9q1jg0mkhxkdthqz78hip72wics8a2ynqm0wzaxwg63jiou0wyliyq00db0pr1icz-2f4iwppkvhjin1zvgwrd7xmmlpxb2lfg4bglhe2bkvqkf1e6edqkpeowldydbfecpd-2bmzzmdpdqqvzeaso8geqnd1zwduko4-3d) published in nature metabolism, the researchers say they discovered how one of the most well-known tzd drugs works at the molecular level and were able to replicate its positive effects in mice without giving them the drug itself. The researchers also were able to identify the specific microrna within the exosomes that was responsible for the beneficial metabolic effects of rosiglitazone, a type of tzd drug. The molecule, called mir-690, eventually could be involved in new therapies for type 2 diabetes, researchers said. Ucsd hall to be named for la jolla resident la jolla resident and businessman brian malk and his wife, nancy, have pledged a philanthropic gift to support the expansion of uc san diego’s department of economics. Brian c. Malk hall, slated for completion in 2026 as part of ucsd’s ridge walk north living and learning neighborhood, will be located in the interior of campus, just west of geisel library. The hall will house the department of economics, part of the la jolla university’s school of social sciences. As the new home to the department of economics, malk hall will include the hub basic needs center and the triton food pantry, which are designed to ensure all uc san diego students have access to nutritious food, stable housing and financial wellness resources. Ucsd looking to buy mcasd building in downtown san diego uc san diego has entered negotiations with the museum of contemporary art san diego to buy the museum’s 8,500-square-foot gallery building in the former baggage building at the downtown train depot at 1100 kettner blvd. The navy seal museum will open in the museum’s other former space, a 10,000-square-foot two-story building in the one american plaza complex at 1001 kettner. According to a statement released by ucsd, mcasd has “entered into a non-binding letter of intent with the university of california san diego to sell the santa fe depot building. ... The parties are in exclusive negotiations, which the parties hope will lead to a final agreement.” The downtown buildings closed last month so the museum could focus on its flagship la jolla campus. — The san diego union-tribune la jolla rowers win local regatta with san diego rowing club the san diego rowing club’s varsity women 1v 8+, featuring students from la jolla high school and the bishop’s school, won first place in the women’s youth 8 b final, beating teams from washington, d.C., Texas and australia, at the april 7 san diego crew classic, considered the largest regatta on the west coast. Sdrc rowers include bishop’s students alex ozarski and grace steinmeier, la jolla high student lindy rumel and other san diego-area students including paige gonor, fallon perry-pelletier, maddie gocal, abby moe, angela king and anne atkinson. World literacy foundation seeking youth ambassadors the world literacy foundation’s new youth-led initiative to help address high rates of illiteracy is seeking san diego-area youth ambassadors. The role — for ages 15-25 — provides a platform to talk about falling rates of reading skills and help increase community education and awareness about the importance of foundational literacy skills. The four-month youth leadership development initiative will provide training and support, plus connection to 600 other young people around the world. “Conscious of the impact of illiteracy, we want to train young people around the world to become change-makers in their own country or region,” said lorena torres, global coordinator for the youth ambassador program at the world literacy foundation. “When we help someone to acquire literacy skills, we are empowering them with access to better opportunities in life and breaking the poverty cycle. We train young ambassadors to help us eradicate illiteracy.” Learn more at [worldliteracyfoundation.Org/ambassador-program](https://worldliteracyfoundation.Org/ambassador-program). —- Compiled by la jolla light staff ? Get the la jolla light weekly in your inbox news, features and sports about la jolla, every thursday for free you may occasionally receive promotional content from the la jolla light.
    ( Read More... | 18600 bytes more | comments? | Printer Friendly Page  Send this Story to a Friend )

     
    KILLING RELIGIOUS FREEDOM IN AMERICA
    Posted on Wednesday, April 17 @ 00:00:09 PDT (9 reads)
    College Guide Killing religious freedom in america much has been made about the transgender day of visibility falling on easter sunday march 31, 2024. The left wants us to think that it falls on every march 31st and it just happened to fall on easter this year. What they dont tell you is that although this holiday has been unofficially recognized since 2009 it was joe biden that signed an executive order in 2021 officially declaring it a holiday but no one really knew that much about it until it the white house announced it with much fanfare a few day before this easter 2024. Why transgenders need a day of visibility makes no sense to me because that is all we hear about these days. There are the other days on the calendar devoted to transgenders and promoting their visibility. International day against homophobia, transphobia, and biphobia, observed on may 17. International drag day is celebrated on july 16. International pronouns day is celebrated on october 17th. Transgender awareness week occurs in november. Transgender day of remembrance occurs on november 20th. Then if you throw in national black hiv/aids awareness day, aromantic spectrum awareness week, whatever that is, national lgbt health awareness week, day of silence, lesbian visibility day, harvey milk day, pulse night of remembrance, celebrate bisexuality day, lgbt history month, national coming out day, spirit day, asexuality awareness week, intersex awareness day, intersex day of remembrance, and world aids day. I would say the alphabet mafia is pretty well visible to the average american. Whether joe bidens proclamation honoring the transgender day of visibility was intended as a slight to christians or not transgenderism is a demonic lie and of course satan is the father of all lies. Speaking to a group of men jesus said “you belong to your father, the devil, and you want to carry out your father’s desires. He was a murderer from the beginning, not holding to the truth, for there is no truth in him. When he lies, he speaks his native language, for he is a liar and the father of lies” john 8:44. Christians make up a vastly larger percentage of the population than people who claim to be transgender but that doesnt matter to the communists/fascists in this country. We are the enemy. there has been a war between christ and satan from before the foundation of the world when christ expelled satan and his angels from heaven. Revelations 12:7 through 11 says 7 and there was war in heaven: michael and his angels fought against the dragon; and the dragon fought and his angels, 8 and prevailed not; neither was their place found any more in heaven. 9 and the great dragon was cast out, that old serpent, called the devil, and satan, which deceiveth the whole world: he was cast out into the earth, and his angels were cast out with him. 10 and i heard a loud voice saying in heaven, now is come salvation, and strength, and the kingdom of our god, and the power of his christ: for the accuser of our brethren is cast down, which accused them before our god day and night. 11 and they overcame him by the blood of the lamb, and by the word of their testimony; and they loved not their lives unto the death. |satan being cast out of heaven| when satan deceived adam and eve he did it by appealing to their vanity. Genesis 3:5 “for god knows that when you eat from it your eyes will be opened, and you will be like god, knowing good and evil.” Because of mans sin we have been plagued little by gods like karl marx, margaret sanger, woodrow wilson, v.I. Lenin, franklin roosevelt, saul alinsky, hillary clinton, barack obama, bill gates, george soros and joe biden who think that they know what is best for the rest of us who have the common sense to know who god is and that we are not him. the assault on religion picked up steam with the advent of communism. A contemporary of karl marx was mikhail bakunin. He said that if god really existed, it would be necessary to abolish him. Bakunin said that religion enslaves, debases, and corrupts, and that all religions are cruel, all founded on blood. Bakunin liked satan however. He hailed him as the eternal rebel, the first freethinker and the emancipator of worlds. This is similar to saul alinskys praise of satan in the forward of his book rules for radicals. Alinsky called satan the very first radical...Who rebelled against the establishment. Saul alinsky had a huge impact on the political philosophies of hillary clinton and barack obama. Cardinal fulton sheen said that communists have failed to convince the world that there is no god but they have convinced the world that there is a devil. Karl marx said that man makes religion, religion does not make man. Religion is the sigh of the oppressed creature, the heart of a heartless world, and the soul of soulless conditions. It is the opium of the people. V.I. Lenin compared religion to necrophilia, which is the perversion of having sex with dead people and he even compared it to a venereal disease. He said that there is nothing more abominable than religion. One of the goals of the communist party was subverting the church. Manning johnson, a black american communist of the 1930s and 40s who later left the party and became a staunch anti-communist said that the party according to my knowledge and experience, realized that without subverting the millions of persons in church, revolution in the united states is unthinkable; it is impossible. For that reason a corps of trained persons was necessary who would be in a position to work successfully toward this end among the churchgoers. The foundation of american society has been based primarily on the strength of the family and the church. Both have been under assault by the left because if the family and church are destroyed people have nowhere to turn to other than the state and this is the goal of the communist party because the state is their god. |mikhail balkunin| so we know full well that communists hate christianity and christians. All we have to do is look back at how many christians have been tortured and killed in the most hideous manner. I had a friend named paul coman who had been a christian living in romania during the communist regime of nicolae ceau?Escu. He was as brutal of a communist that ever was. Paul was possibly the most dedicated christian that i have ever known. He was arrested by the secret police and placed in a cell so crowded that he could not sit or lie down and the lights were kept on 24/7. He was savagely beaten and tortured. One method of torture they used on him was standing him in a hollowed out tree and bending him backwards. After he finished his jail sentence they dropped him off a few miles from home barely conscious and a living skeleton from malnutrition. He managed to crawl all the way home on his hands and knees where his family nursed him back to health. We became friends after he escaped to the united states. One day i took him on a tour of the tennessee state museum in nashville. I was amazed when we toured the section displaying how the early settlers of nashville lived in the late 1700s. He explained to me in detail what everything was used for because his country was so backward under communism that their people were still using the same primitive tools that our ancestors in americas pioneer days were using over 200 years ago. Paul was one of the millions of christians persecuted by the communists since the bolshevik revolution in russia 1917. Many were tortured so severely that they renounced their faith and their torturers did blasphemous things like forcing christians to take communion using urine and human feces rather than wine and bread. One christian in romania named florescu was beaten and prodded with red hot pokers. Starving rats were released into his cell and he had to continually fight them off. He had to watch as his 14 year old son was beaten in front of him. They wanted florescu to renounce christ and the father told his son that he wanted to give in because he couldnt take seeing him beaten anymore. Florescu said that he would do what they wanted him to do. The son responded father, dont do me the injustice of having a traitor as a parent. Withstand! If they kill me i will die with the words jesus and my fatherland. In a rage his captors beat his son to death splattering his blood all over the cell. Florescu survived but was both physically and mentally scarred for life. the communists in russia, eastern europe, china and communist nations all over the world hate all religions, especially the big three. Christianity, judaism and islam. In western europe and the u.S. The cultural marxist movement pushes the idea that there are two classes of people. The oppressed and the oppressors. The oppressors are white christians and jews. This is one reason that there is so much antisemitism in the democrat party today and many democrats are anti israel. Many leftists mistakenly believe that most jews are white. There have always been native palestinian jews that are as dark as any arab people. People of color, homosexuals, bisexuals, transsexuals and muslims are seen as the oppressed. The communists promote the spread of islam in the western world because it is so diametrically opposed to christianity. It serves their cause to allow the spread of the islamic religion in the u.S. For now yet the communists persecuted islam in the soviet union and the chinese communist party persecutes the islamic people in china today. If there is ever a total communist takeover of america islam will be persecuted the same as they are now in china. For the time being in western europe and america promoting the spread of islam is seen as destabilizing to the traditional judeo christian ethic and it is supported by the communists/ fascists. Atheism is the fastest growing religion in america today. The god that they worship is man and by extension the state. There is nothing higher. Contrary to what leftist historians will tell you america was founded on the judeo-christian ethic. Even the founding fathers who were religious skeptics like benjamin franklin realized the importance of religion in society. Bidens new diversity czar zakiya carr johnson just said that america is a failed historic model and demanded the destruction of tradition at every juncture on the altar of antiracism. This also means americas judeo-christian tradition which has been, along with the family the stability of american society. Her words are straight out of the communist playbook which makes her a neo-marxist. In 2008 when obama said that he wanted to fundamentally change america this is exactly what he meant. Karl marx would be very proud of his accomplishments so far. the destruction of americas judeo-christian ethic could be traced back to the latter half of the 19th century. Horace mann introduced the public school system to massachusetts when he became secretary of education there in 1837. The concept of public schools would later spread to the entire country. He based his educational reform ideas on the german model of a more centralized and secular educational system. Americas educational system had been modeled after the greek paideia prior to the ideas of mann. It is essentially the part of upbringing and education that forms the soul of a human being — and it is key to the formation of a culture. The core curriculum was the seven liberal arts. They were rhetoric, grammar, logic, astronomy, arithmetic, geometry and music. The greeks designed their educational system to be available to all classes of people rich and poor. Through critical thinking man could ultimately discover god. After europe became christian the greek paideia became the christian paideia and this system made its way to america. Manns system would teach children what to think. The christian paideia taught children how to think. They were more likely to reach their own conclusions. The great thinkers such as plato, socrates, aristotle, rousseau, montesquieu, hume, locke, adam smith, our founding fathers, lincoln and other early 19th century figures were beneficiaries of the christian paideia. Lincoln had probably no more than a second grade education but he learned the process of critical thinking. Although many poor people in rural and urban early america did not have access to education because their labor was required to make ends meet the ones who were educated received a top quality education. All you have to do is read the letters of an educated ten year old from that period. Their use of grammar would put a modern college professor to shame. We have access to more information and an education today than any period in world history but far too many of our people are illiterate and ignorant. Being ignorant simply means that they lack knowledge. Many though are willfully ignorant which makes them stupid. Children are routinely graduating from school today who cant read and write. Or they cant make change at mcdonalds. As a security supervisor i had incident reports on a routine basis that were so poorly written that i couldnt even decipher them or turn them in. The communists/fascists want us to be uneducated because it is virtually impossible to control a highly educated populace. That is a population who are educated to think for themselves and not those who are brainwashed by indoctrination. beginning in the late 1800s, with the growth of manns public school system and other progressive educational reformers like john dewey over time america saw the virtual death of the christian paideia and critical thinking. Mann promoted normal schools that were colleges built for the sole purpose of educating teachers. Although public education was nonsectarian or affiliated with any religious faith the administrators and teachers had a healthy respect for religion. They understood the importance of religion regarding the molding of character in young people. The school day would usually start with a prayer or bible readings and prayers were routinely said prior to special school events such as graduation ceremonies and athletic events. Nobody freaked out if a teacher read the bible in class or conducted bible studies in class. This all began to change with a supreme court decision called everson vs. The board of education in 1947. if you ask most americans whether or not there is such a thing as a separation of church and state they will say yes because it is in the constitution. They would be wrong, however. There is no such thing as separation of church and state in the constitution. The first amendment is very clear. It reads that congress shall make no law respecting an establishment of religion, or prohibiting the free exercise thereof. What this means is that congress cannot establish a national religion and that it cannot prohibit anyone from worshiping the way that they please. National religions were common in europe and america was going to be different. The founders never intended for church and state to be completely separate. They considered religion indispensable to the nation that they were creating. The phrase separation of church and state comes from a letter that thomas jefferson wrote to the danbury baptist association as president in 1802. Although jefferson believed that religion should be a private matter he also understood how indispensable religion was to our nation. Thomas jefferson and james madison worked to disestablish the anglican church as the state religion of virginia which was written into law in 1786. Yet thomas jefferson and james madison would never try to tell another state how they should approach religious liberty in their own state. Before everson vs. The board of education each state determined its own approach to religion. For example the state of tennessee could legislate that the catholic church or the baptist church, or any denomination could be their state religion. I would not be in favor of a state religion but any state in the union could have a state religion if they wanted one and the federal government could not do anything about it. They could also have public prayers, display the ten commandments on public property and government buildings. Menorahs or christian displays could be allowed on public property and in government buildings. This is the wall of separation that jefferson talked about in the danbury letter. The wall of separation between the federal government and the individual states. In 1947 the supreme court, in a 5 to 4 decision changed the original meaning of the first amendment. The ruling stated that neither a state nor the federal government could pass laws which aid one religion, aid all religions, or prefer one religion over another. A modern strict separation view was born. The five justices did not look to the constitution for the source of their ruling but to jeffersons danbury letter and they totally misunderstood what jefferson was trying to say. It was ironic that they would misconstrue the words of the man who wrote the declaration of independence. The same man who wrote we hold these truths to be self evident that all men are created equal and endowed by their creator with certain unalienable rights, that among these are life, liberty and the pursuit of happiness. As joe biden might say you know the thing. He is also the same president who attended a christian church in the u.S. Capital for the entire eight years he was in office. Incredibly jefferson was being used as a pawn to separate religion from the public square. |benjamin franklin, john adams and thomas jefferson with the declaration of independence| the nations moral infrastructure began to crack after everson vs. The board of education ruling. Liberal justice william o. Douglas wrote in a court case in 1952 that we are a religious people whose institutions presuppose a supreme being. This is something that the founders would have strongly agreed with. Religion in the public domain suffered another great blow in the years 1962 and 1963. In 1962s court case called engel vs. Vitale the supreme court ruled that a generic school prayer violated the courts new definition of the 1st amendment. The prayer went like this. Almighty god, we acknowledge our dependence upon thee, and we beg thy blessings upon us, our parents, our teachers, and our country, amen. In june 1963 a case called abington school district vs. Schempp the supreme court ruled that bible readings and prayer in school were unconstitutional. Is america better off since the early 1960s? Not according to statistics. Marriage rates have fallen, birth rates have fallen, the numbers of americans giving to charity have fallen. On the other hand the numbers of children being raised without fathers, behavioral problems in school, and crime has risen dramatically since the end of prayer in school. Divorce rates have risen as well as the number of children born out of wedlock. Many of the key players in the destruction of americas moral infrastructure are despicable people. Karl marx was a worthless moral degenerate and you can read his backstory in my article entitled killing common sense published on november 9, 2022. The supreme court justice hugo black, who was the chief designer of the everson vs the board of education ruling, and is still a hero of the so called progressive left, was a former member of the ku klux klan who hated blacks, catholics and jews. It was his hatred of the catholic church that motivated him to design the ruling that overturned the original meaning of the first amendment regarding religious liberty. You can read more about him in my article entitled the beginning of the end of religious freedom in america. Then there was madalyn murray ohair who had a lot to do with one of the lawsuits banning the reading of the bible and saying prayers in public schools which was abington school district vs. Schempp. She was an angry atheist and communist who had tried to defect to the soviet union just before her lawsuit against the baltimore city school system. Her son william j. Murray was used as an unwilling pawn in her lawsuit as a child and he is now a pastor and serves as the chairman of the religious freedom coalition. You can read about madalyn ohair in my article the angry atheist published may 27, 2018. I would highly recommend pastor murrays book let us pray in which he goes into much detail about his mothers sordid past and what it was like to be raised by such a dysfunctional person. i realized many years ago now that there was a war on religion in this country. As a child, and as a young adult i remember many religious symbols such as nativity scenes, menorahs, and crosses on city and state property. The state capital would be decorated every christmas and you would see religious displays during the holidays in public schools. One of my fondest memories as a child was harveys nativity scene that flanked the south side of the parthenon. It was there for years and people would travel miles to see it. For me christmas was not the same if i didnt get to see it at least once before christmas. Fred harvey junior eventually sold it to a foreign buyer because of the expensive upkeep. Because of the aclu and other communist groups it would not be possible to have this nativity scene today because centennial park is city owned property. Another fond memory that i had was how the l&c tower, which was our first tall building in nashville, would turn all the office lights out except for lights that made the figure of a cross at christmastime. The life and casualty insurance company is privately owned but they discontinued this practice years ago. Unfortunately i was probably in my late forties when i finally realized that the everson vs the board of education ruling in 1947 was a false interpretation of the 1st amendment regarding religious liberty. This false interpretation is what i was taught in school. It was pastor bill murrays book, let us pray that opened my eyes to the fact that there is no separation of church and state. The aclu and other groups have made much progress in the war to destroy religious liberty in this country. If there has been any doubt to what demonic forces we have been fighting over the years the covid lockdowns should have opened a lot of eyes. |harveys nativity scene| |the tennessee state capital at christmas| during covid lockdowns liquor stores were allowed to stay open because they were considered essential but church services were banned. Alcohol and drug related problems increased during the covid lockdowns as well as the number of suicides. During the height of covid and during the george floyd riots rioters and protestors were encouraged by leftist mayors, governors and government officials to be in the streets but again churches were locked down. Pastors were arrested for violating lockdown orders. Some in front of their church congregants. One of the most ridiculous arrests i saw was people who were in their cars at a drive in church in mississippi. In the past few years there has been a rise in anti christian rhetoric. More and more churches are burned and vandalized. Canada has had a wave of church burnings. The biden doj has declared war on the church. They are monitoring bible sales. The doj is also monitoring catholics who prefer the traditional latin mass. Most christians are being targeted as christian nationalists and by extension domestic terrorists. We are the bitter clingers that obama talked about. You know, the people that hold on to their religion and their guns. Yes, you can call me a proud bitter clinger. I am a christian and i love my country. What real christian doesnt? They try to make it racial by calling us white christian nationalists. Okay, i will take the bait. I am white, i am a christian, and i love my country. At least i hope i love my country because i served 21 years defending it. I raised my hand to swear allegiance to its constitution at least five times. My allegiance to the constitution didnt expire upon my discharge from the armed forces. Yes, i believe that all men are created equal and endowed by their creator with certain unalienable rights that among these are life, liberty, and the pursuit of happiness. These words are anathema to biden and the communist/fascist left. My god is the one true god and their god is the state. There is nothing higher than that to them. The early christians werent fed to the lions in rome because they believed in christ but because they wouldnt swear allegiance to caesar. I trust the fate of american people in the hands of a christian nationalist government more than i trust their fate in the hands of a secular communist/fascist government. Even when so-called christianity was at its worst in europe and america during the spanish inquisition and the burning of witches a few thousand people lost their lives over several centuries. Over 100 million people died at the hands of the atheist communists during the twentieth century alone. elections have dire consequences. America can vote biden back into office this november and hasten the demise of religion in this country. Yes trump is a heathen and hurts the feelings of suburban women with his harsh tweets but there has been no president more friendlier to religion in america perhaps since ronald reagan. God sometimes uses the most unlikely people to further his cause. Trump had the moral fortitude to place our embassy in jerusalem. Something that has been promised by a multitude of presidents since 1967 but has never been done until donald trump did it. Trump will not be weak and wishy washy with his support of israel like biden has been trying to placate his islamic voting block and brainwashed antisemitic leftists. The bible is clear about who the victor will be in the war between christ and satan. Spoiler alert. It wont be satan and his evil followers. Yet we also know that things are going to get pretty rough for his people here on earth before christ wins the final victory. We are definitely in the final days but we havent seen anything yet. We do have the ability to slow that process down based on the actions of righteous people. That is why this election is so important. Regardless of what happens we know that the lord is with us. Psalm 27:1-the lord is my light and my salvation-- whom shall i fear? The lord is the stronghold of my life-- of whom shall i be afraid? When evil men advance against me to devour my flesh, when my enemies and my foes attack me, they will stumble and fall.
    ( Read More... | 53226 bytes more | comments? | Printer Friendly Page  Send this Story to a Friend )

     
    Upcoming Events

    Classifieds

    R/C Helicopter
    Get yourself an rc helicopter at TrendTimes.com

    Watch the video!

    Phone Numbers
    Yellow Pages

    White Pages

    Past Articles
    Wednesday, April 17

  • Rewind: News from the last 7 days
  • List of episodes by production order
  • Corrupt Leftwing Soros DA Alvin Bragg Threatens Trump With 30 Days of Jail Time
  • Advanced BioFuels USA – Diesel-RANGE – A 5-Letter Word for EARTH MONTH
  • How education and social media regulation can combat science denial
  • Column: What my 6,994-day streak of no Snapchat has taught me about communicatio
  • class=”pg-headline”>She had no sanitary pads. No one knew and no one helped
  • Smartphone messages strongly reduce blood pressure through spirituality
  • Dirty Soes
  • La Jolla News Nuggets: Free-speech pads, Scientist of the Year, Tour dElegance p
  • Where is Ecuador going after international “embarrassment”? – DW – 04/16/2024
  • Student suspended for using term ‘illegal alien’ in English class
  • What Is a Prison?
  • Regulating Tumor-Associated Macrophage Polarization by Cyclodextrin-Modified PLG
  • KILLING RELIGIOUS FREEDOM IN AMERICA

    Tuesday, April 16

  • The Rest of The Novel
  • matej roth
  • Engineer I or above IBEW 949 - Welch, MN
  • AGRAWAL: Stop normalizing vape culture
  • What’s the inside track on protein powder? Nutrition specialists share 3 issues
  • Transparent to Transcendence
  • professional report ghostwriting for hire usa
  • asher denham
  • Innovent Announces the Appointment of Dr. Nageatte Ibrahim as the Oncology Chief
  • brian griffing
  • 10 insights on todays news that will make you smarter tomorrow
  • degeorge & contreras
  • A memoir explores a shattering childhood and narrow escape
  • graham myers
  • Advanced BioFuels USA – SHIFT – A 5-Letter Word for EARTH MONTH

    Older Articles




  • All logos and trademarks in this site are property of their respective owner. The comments are property of their posters, all the rest © 2001 by CollegeHighway.com