#nrk 16
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“The Couple Next Door” at MIPCOM 2023 in Cannes 🇫🇷
Beta Film distributed “The Couple Next Door” series, the Beta Film drama series was sold before the MIPCOM’s event to Movistar Plus+ in Spain and Nordic countries, public television stations NRK in Norway, YLE in Finland, SVT in Sweden, DR. in Denmark and RÚV in Iceland took the title.
The official thriller of the dark psychological drama ‘The Couple Next Door’ (6x1h, Eagle Eye Drama/Beta/Channel4/STARZ/LIONSGATE+) delves into the repercussions of pursuing one's darkest desires. Sam Heughan and Eleanor Tomlinson partner with Alfred Enoch (Harry Potter, How to Get Away With Murder) and Jessica De Gouw (The Secret She Keeps) was presented on Tuesday 17th October at The World Greatest Gathering of TV & Entertainment Executives 16-19 October 2023 at Palais des Festivals, Cannes.
#thecouplenextdoor show will launch this autumn 2023, there's no date, on Channel 4 in the UK, Starz in North America and Lionsgate+ in Latin America. Filming took place earlier this year in Leeds and Belgium, and Beta Film is the distributing.
BETA Unveils MIPCOM 2023 line-up with over 20 new dramas and seasons from 15 countries - Thrillers, about tragedies, and love stories of fresh and compelling series from all over Europe, which will celebrate its world premiere at the prestigious Grand Auditorium of the Palais de Festivals in Cannes.
MIPCOM CANNES 2023- (Marché International des Programmes de Communication, English: International Market of Communications Programmes) is an entertainment content market', and happens every October, MIPCOM is the most anticipated week for global decision-makers to compete for new series, source international production partners, and set the development agenda for the coming year and beyond.
The 39th edition of MIPCOM CANNES brought together more than 12,000 delegates from over 110 countries, including 3,000 buyers, to the vibrant city of Cannes.
Because of the BAFTA’s event, I believe the TV Preview and official thriller to the public will not be available until Wednesday 1st November in London (it makes sense to show everything in one day) with cast Sam Heughan, Eleanor Tomlinson, Alfred Enoch, David Allison, writer, Dries Vos, director as announced, at the Princess Anne Theatre.
youtube
#thecouplenextdoor #thriller # BETA #Cannes #MIPCOM2023 #France #PalaisdeFestivals #InternationalMarketofCommunications #Channel4 #EagleEye
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Moose from Ringsaker
Part of the rock carvings on a rock on Stein farm in Ringsaker, Norway. The whole rock depicts a total of 16 moose, which were carved around 5000- 6000 years ago.
NRK arcticle on the rock
The rock on Kulturminnesøk, (a search engine for norwegian cultural monuments)
If you happen to know what distinguishes these figures as moose and not some similar animal, please tell me i would love to know <3
#stone age#neolithic#norway#petroglyph#rock carving#scandinavia#archaeology#moose#cervidae#elk#bronze age#illustration#digital art#artists on tumblr#really starting to like this flaming petroglyph thing i've got going on#instead of the traditional red
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December 12th marked 10 years since the first released song by AURORA was released!
Song Puppet, professionally recorded in a studio with Thomas 'TomTom' Haugland, was a Christmas gift for her parents. After being posted on Facebook, the song was uploaded by a close friend without AURORA's permission to Norwegian demo music site NRK Urørt, and from there it then went viral in Norway! The rest, as they say, is a history...
Below you can read a translation of the article for the local newspaper Midtsiden, translated by Gandalvr:
Debutant tops the charts on Urørt
Aurora Aksnes from Os has recently recorded her first song. Two days after uploading to NRK Urørt, she topped the list.
On Wednesday 12 December, Aurora Aksnes (16) uploaded a newly recorded, self-written and self-composed song on Facebook, the first song she has recorded.
A friend took the audio file and uploaded it on NRK Urørt, and before the weekend the song “Puppet” was at the top as the Untouched of the Week.
– I had never dared to upload the song myself, Aurora laughs, surprised and happy with the response.
At the time of writing, 2,991 have already listened to the song.
Mostly dancing – until now
Aurora has been a student at Os kulturskule (cultural school) for the last 2–3 years, but she has been studying dance, not song.
– But I have been singing for as long as I can remember, and have been writing songs for several years now, the young song talent tells us.
She has nevertheless, to date, had a small audience. The only thing she has done on a stage before is dancing with other of Patricia Langeland’s students, including at UKM (The Norwegian Youth Festivals of Art).
In 2011 she was part of the elite group that went on to the national finals in UKM in Trondheim.
Teacher tipped her about TomTom
Aksnes is a student at Nordahl Grieg, where she will study music when she starts 2nd grade.
It was a teacher at Søfteland junior high school who encouraged her to go to the studio, and who suggested the osing [someone from Os] Thomas “TomTom” Haugland, who among other things produces for his girlfriend, Myrna Braza.
– I have just been in the studio, and it was exciting. TomTom was very helpful, Aurora says.
– It was great fun to work with Aurora, we’ll probably see much more from that girl, says Haugland.
– She is young, but knows how she wants it. At the same time, she was good at listening and open to input, TomTom says.
Has over 30 of her own songs
Aurora, who plays the piano on “Puppet”, says that she writes all the songs herself.
– Now I’m up to 32 songs, and I have several ideas that I have not yet put down on paper.
– What are you writing about?
– I know that life can be both good and bad, and I think it is important to bring out the shadowy sides as well.
– That’s why I choose to write about this, and I hope someone can recognize themselves in my lyrics, says the young and talented songwriter Aurora Aksnes.
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Language Learning Log 2023
Week 28 (10/07~16/07)
Japanese
It's been nice not having to worry about the JLPT. I've focused a lot on writing this past week, including handwriting in my journal without a dictionary (as well as writing in my notebook with a dictionary and kanji how-tos at my disposal). I mostly just try to use what I know and maybe double-check kanji or grammar occasionally, perhaps look up a new word every now and then, rather than looking up lots of things to try and accurately express myself. I realised I takes too long and I just forget it anyway, so it's better to reinforce what I've already learned and add onto those foundations slowly. Japanese is not a language I can rush through learning and I need to review constantly!
I'm also trying to read a bit more (not lots because it's still very overwhelming, but a little bit here and there). I'm getting better at it and sometimes - with context and occasional help from a dictionary - I can more or less get the gist of articles on NHK Easy News. I always feel proud of myself when I don't need to read the furigana, which is happening more and more!
Norwegian
I've started trying to watch things in Norwegian again. Just short things: interviews, NRK Humor videos, the likes. I expected to struggle because I don't do much listening these days, but I found I'm still able to forget I'm watching in a second language a lot of the time (providing the dialect's not too thick). Watching things has reminded me that while my grammar and vocabulary are sufficient for everyday life, I still don't phrase things entirely naturally, so it's important I keep up the listening practice. Even just watching one 2-3 minute video a day is good! It doesn't have to be a full 25-minute episode of a show.
#progress report#language learning log#langblr#norwegian langblr#japanese langblr#learning languages
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Hi, do you know if there any English translation for the series 17? Thanks
If you mean the Norwegian NRK series called 17, you can find the whole show on SVT Play with Swedish subtitles (using a VPN). They're burned-in though, so you can't really do the old Google Translate auto-translate trick to make them translate into English or download any SRT files.
This show is also incredibly confusing to find. Apparently season 1 is known as 17, season 2 is known as 18, season 3 as 16, and the final fourth season as 19. From what I understand the show is called 16–19 but is commonly known as just 17. On SVT Play the title is for some reason listed as 19.
If anybody does know where this show can be watched with English subtitles, do let me know!
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USAF's CV-22 Osprey is "stuck" in a nature reserve in Norway 🇳🇴
Fernando Valduga By Fernando Valduga 09/03/2022 - 09:56in Incidents, Military
A USAF Special Operations Osprey CV-22 is unable to take off at the Stongodden nature reserve, on the island of Senja, in Troms (Norway).
The aircraft, CV-22B (10-0053), belonging to the 7th Special Operations Squadron 'Aircommandos' based in Mildenhall (United Kingdom), made an emergency landing on the spot on August 12, 2022.
Since then, Osprey has been stuck on the island, as repairs on site are considered impossible, as reported by the Scramble publication.
Norwegian authorities are investigating several options to rescue the plane from the nature reserve, in constant contact with U.S. authorities.
"From now on, the sea route is Plan A," Chief Sergeant Odd Helge Wang of Air Wing 139 of the Norwegian Armed Forces' Maritime Helicopter Wing told the Norway Post. "It is quite complicated to accomplish technically, and something that neither we nor the Americans have done before."
"We hope that a decision will be made by them during this or next week. Once taken, it will take about two to three weeks to perform the operation," says Wang.
Colonel Eirik Stueland told the NRK publication that a road, a ramp and a pier must be built in the nature reserve to transport the aircraft.
The Norwegian Defense Forces propose to put carpets on the ground, in order to be able to approach the machine without destroying the ground. But putting it on a boat will probably not be an easy task.
The locally very shallow coast makes it very difficult to bring a transport barge nearby. In addition, the Norwegian climate is not helping.
"It's very shallow in the area, so there are problems in taking the boat far enough. A 70-meter-long crane arm is required," says Wang. "In addition, we have to take into account the climate. There can be no waves more than 0.3 meters high or winds more than seven meters per second."
The operation will cost a "significant" amount, he says.
In addition to all this, experts need to take into account environmental damage, since the aircraft is in an ecological reserve.
"We're probably talking about millions. But it is the Americans who have to pay the bill because it is their machine," Wang adds.
AFSOC has more than 50 Ospreys in its fleet, currently at the air bases of Cannon, N.M., Hurlburt Field, Florida, Kirtland, N.M., RAF Mildenhall, United Kingdom, and Yokota, Japan.
Tags: AFSOC - Air Force Special Operations Command/US Air Force Special Operations CommandMilitary AviationAir IncidentsUSAF - United States Air Force / US Air ForceV-22 osprey
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Fernando Valduga
Fernando Valduga
Aviation photographer and pilot since 1992, he has participated in several events and air operations, such as Cruzex, AirVenture, Dayton Airshow and FIDAE. It has works published in specialized aviation magazines in Brazil and abroad. He uses Canon equipment during his photographic work in the world of aviation.
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185：底名無し沼さん (ﾜｯﾁｮｲ 1903-VVzI)：2024/01/05(金) 21:54:34.64 ID:GVN3cPfY0
寝る前に山岳小説を読みたいのですが
おすすめはありますか?
192：底名無し沼さん (ﾜｯﾁｮｲ b27b-e1ln)：[sage]：2024/01/06(土) 08:11:25.09 ID:k9pvmqdg0
>>185
ちょっと古いが木暮理太郎
青空文庫でも読める
220：底名無し沼さん (ﾜｯﾁｮｲ dff3-zynb)：2024/01/08(月) 21:25:24.86 ID:a98F5DMk0
>>185
青空文庫に古い名著があるね。
木暮理太郎
田部重治
あ、尾崎喜八は著作権の問題で取り下げかな。
224：底名無し沼さん (ﾜｯﾁｮｲ 7f6c-ODQj)：[sage]：2024/01/09(火) 12:29:37.91 ID:+pUouzK40
>>220
192だけど木暮理太郎は随筆とか紀行文なのかも知れんね
山岳小説だったら栄光の岩壁が好きです
234：底名無し沼さん (ﾜｯﾁｮｲ ff6e-zynb)：2024/01/09(火) 22:45:53.42 ID:KaIfPp7I0
>>224
あ、すまん、山を舞台にしたフィクションの意味かな？
栄光の岩壁って何だっけと思ったら芳野満彦モデルのだっけ。
それなら新田の他全部、と言いたいけど、ごく少数以外絶版みたいで、古本屋であまり見かけないな。
山岳推理系の梓とかあるけど、性に合うかな？ それも多いとはいえないし、どこでも在庫があるとは考えにくいし。
仕方ないから古本屋で、100円コーナーから手始めに、山関係のタイトルとかで、それらしいのを手当たりしだいに探すしかないんじゃない？
そういえば中学の頃に山月記を山日記と勘違いして買って読んでアリャリャとなったことがあったな。
あれはあれで読み応えはあったけど。
186：底名無し沼さん (ﾜﾝﾐﾝｸﾞｸ MM92-2474)：[sage]：2024/01/05(金) 22:00:09.11 ID:AJwaoeUnM
植村直己
188：底名無し沼さん (ﾜｯﾁｮｲ 42fc-Y7tG)：2024/01/05(金) 23:56:28.49 ID:fzz35Tj00
植村直己みたいな登頂実録物もいいけど「山岳小説」と言ったら新田次郎だろ
俗に言う三部作は長編だけどどれも読み応え十分で引き込まれて長さを感じなかった
他には夢枕獏の神々の山嶺とか
189：底名無し沼さん (ﾜｯﾁｮｲ 190e-ENrn)：[sage]：2024/01/06(土) 00:38:13.58 ID:syBuXndN0
外道クライマー
191：底名無し沼さん (ﾜｯﾁｮｲ f52c-nrks)：[sage]：2024/01/06(土) 03:40:18.78 ID:JN27hNyK0
山岳小説じゃなけりゃ原全教の奥秩父とか結構楽しいんだけどね
山岳小説はよく分からん
194：底名無し沼さん (ﾜｯﾁｮｲ 0676-ENrn)：[sage]：2024/01/06(土) 15:58:15.11 ID:Pfwf8lm50
神々の山嶺は面白いよな
女捨てて密入国+違法登頂アタックしたカスの話ではあるけど
195：底名無し沼さん (ﾜﾝﾐﾝｸﾞｸ MM92-2474)：[sage]：2024/01/06(土) 16:44:56.76 ID:u487BQdUM
神々の山嶺の映画見たけどよく分からんかったな
エベレスト初登頂のフィルムを追ってたはずなのに
途中からどうでも良くなっててなぜかエベレスト登ってた感じだったわ
199：底名無し沼さん (ﾜｯﾁｮｲ b24e-KcZb)：[sage]：2024/01/06(土) 22:51:44.96 ID:iFOLEKpu0
>>195
自分が読んだのはあくまで漫画版だが映画はだいぶ端折られててイマイチだったな
マロリーのフィルムを巡るいざこざと羽生丈二の生き様を2本の柱として展開する物語なんだが
前者はほぼ全面カットで後者に関してもいざこざの中で見える部分は消えてるし
あとなんか恐怖地味た演出と陰鬱な雰囲気で漫画版の孤高の人の方が近いんじゃないかと思ったわ
196：底名無し沼さん (ﾜｯﾁｮｲ 62df-MLI3)：[sage]：2024/01/06(土) 22:19:14.01 ID:dRHqWSL40
深田氏の日本百名山があるではないか
197：底名無し沼さん (ﾜｯﾁｮｲ 42d1-GefU)：[sage]：2024/01/06(土) 22:34:30.60 ID:pm7AahSq0
あれ小説と捉えてるん？
198：底名無し沼さん (ﾜｯﾁｮｲ 62df-MLI3)：[sage]：2024/01/06(土) 22:43:02.89 ID:dRHqWSL40
あっ随筆ってやつか
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MUSIKK: Simen Steinklev ute med låta "Bare for i dag"
Simen Steinklev har markert seg som et av de mest spennende nye navnene i den norske musikkfloraen, med sin smittende energi og varierte lydbilde.
23-åringen ble kåret til månedens urørt av NRK P3 i januar, etter han i 2022 vant hele den internasjonale finalen i konsert-konkurransen Emergenza, med norsk rap! Steinklev begynte å rappe på ungdomsklubber i Arendal som 16-åring, og har med tiden…
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NRK-trollet håner oss lyttere med sine nyhetssendinger: Dagsnytt 23/9-2023 kl 16:00 - P2
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January's classic experience: A classic saga of January's good-old adventures (prior to the Pokémon experience) - Part 16 = {Driving Ib and Ib - Part 16 🠊 The Triss team's sitcom show - Part 16 🠊 Parody adventures with Luffe and Sjanne - Part 16 🠊 The Angora guys by night - Part 16 🠊 Fritz and Poul (ft. Split) records their livestream commentary for "January and co.'s hero-brave sad-to-fab quest thru their hero-brave journey from sad to fab" - Part 16} ▶ [Mr. Müller's audio/video commentary for "January and co.'s hero-brave sad-to-fab quest thru their hero-brave journey from sad to fab"] January's hero-brave journey from sad to fab - Part 16 = [Mr. Schüster's audio commentary for "January and co.'s pre-historic quest"] January and co.'s pre-historic quest - Part 16 = January reads some funny signs - Part 4: January states that it's unfair / January decides to become hero-brave / January becomes hero-brave / January begins a new day / January meets Anita / January and Anita meets some new friends / Make way for January and co. / January and co. begins their adventure / January and co. engages some funny signs - Part 1: January and co. engages into an embryonic funny sign journey
And now, back to the show.
...
682.682.682.January gets an funny sign hangover
683.683.683.January has yet another more crazy illegal funny signs
684.684.684.January gets some funny signs mayhem of fireworks
685.685.685.January sneaks some funny signs in the car
686.686.686.January captures some funny signs footage
687.687.687.January meets some hot-or-not funny signs
688.688.688.January are still having trouble with some funny signs
689.689.689.January gets arrested by those funny signs
690.690.690.January hacks the cash of funny signs
691.691.691.January are still spending too much time of funny signs
692.692.692.January glitches some more funny signs
693.693.693.January gets paralyzed by some funny signs
694.694.694.January glitches another more funny signs
We're continuing where we had left off.
After already too much hard time of reading too many funny signs, the wait is finally over, and because of that, January are about announce that he is going to be hero-brave, as well as famous and fabulous, cause he (at the same time) declares his hero-braveness, by plotting an hero-brave scheme of hero-braveness from bad mood to good mood as well as from sad to fab. So now, without further ado, January are about to retreat his hero-brave dreams of hero-braveness, so that he can become hero-brave, famous and fabulous. Well that's enough with the set, so for now, without further ado, let us get into business.
And we'll continue on...
695.695.695.January plots an hero-brave scheme of hero-braveness from bad mood to good mood as well as from sad to fab
696.696.696.January gets ready to train his hero-brave career (in the style of Mister Rogers' Neighborhood (from 9 June 1948 to 31 August 2001))
697.697.697.January makes himself hero-brave so that he can be brave and bold (in the style of official broadcasts from: RTP (from May 1930 to 19 February 1993), RTÉ (from 1 January 1926 to 19 September 1998), RÚV (from 20 December 1930 to 8 October 1986), RTBF (from 18 June 1930 to 11 September 1987), SRG SSR (from 30 September 1922 to 30 August 2006), RAI (from 8 February 1923 to 23 September 1974), RTVE (from 19 January 1937 to 24 January 1990), BBC (from 18 October 1922 to 1 November 1982), YLE (from April 1923 to 31 December 1992), GRF (from June 1884 to 5 April 1987), NRK (from 1 November 1922 to 4 September 1992), DR (from 1 April 1925 to 30 September 1988), VRT (from 18 June 1930 to 24 August 2000), NPO (from 6 November 1989 to 31 August 1995), SRT (from 21 March 1924 to 14 September 2007), and ARD and ORF (from March 1892 to 31 December 1983))
698.698.698.January are luckily making it smart (in the style of official broadcasts from: HTV (from 14 January 1958 to 31 December 1992), Yorkshire (from 22 September 1955 to 20 October 1996), Tyne Tees (from 15 January 1959 to 1 September 1996), Granada (from 22 September 1995 to 31 December 1994), Central (from 22 September 1955 to 5 September 1999), Westward/TSW (from 29 April 1961 to 31 December 1992), Southern/TVS (from 30 August 1958 to 31 December 1992), and Thames (from 22 September 1955 to 31 December 1992))
699.699.699.January can always be so proud of getting so much time to sphere (in the style of classic Ragdoll Productions episodes prior to 1993 (from the first "Puzzle Party" in 1977 to "1992: Year in Review" on 31 December 1992) (including the old TV-am (from 1 February 1983 to 31 December 1992)))
700.700.700.January collects a lots of awesomeness (in the style of Daneboe's classic videos prior to 1 January 2011 (from "Pugzilla" to "Annoying Orange: Wishful Thinking"), Davemadson's classic videos prior to 7 October 2011 (from dnm728's early videos to "The Adventures of Microsoft Sam and Friends - Episode 2: Broadcast News" (alongside some classic TTS-produced video uploads from the early Windows 3.0 beta build 1.11 to 6 October 2011 (including some random-shitting Funny Signs accents of various videos from Daneboe's video archive (from "Pugzilla" to "Annoying Orange: Fake N' Bacon")))))
We're continuing where we had left off.
January are so excited to collect so much hero-braveness, as well as some awesomeness, cause he had successfully turned out to be hero-brave, and due to that, he can't wait to become hero-brave, famous and fabulous, cause January will always make his dream come true, just like that. We'll anyway, January are obviously interviewed by a machine at the money company. A few minutes later, Gary Gadget and Freddy Ferrick are new anchors, while Conrad Cupman reports of heavy flooding and January flubs his farm report.
And we'll continue on...
701.701.701.January's typical situation
702.702.702.January's training workout
703.703.703.January gets a job interview
704.704.704.January broadcasts an special bulletin
We're continuing where we had left off.
The next day, January refixes his smartphone and are apparently taking a stroll in the town. Well then, at a lucky moment, he luckily meets a beautiful girl named Anita. Anita makes her first appearance (since checkpoint #125 for which January were resuming his workout), cause she becomes January's girlfriend, so that they can be best friends, just like that. In that case, January are getting a psychology treatment by Anita because with 2 problems caused by 4 previous checkpoints (which were 701, 702, 703, and 704), well besides, January consults Anita, a registered therapist, to help him get over his anxieties, and then afterwards, the two friends are getting their first date, well for some reason, January are obviously explaining that they won't have to find their way back home to Berlin, so instead of that, they will just rather find their way back home to Vienna (which is the capital city of Austria), cause January are constantly hoping that he (along with Anita) will both soon guide their way back home to Vienna. At that case, as January knows that the starlights are meant for him, January (along with Anita) are both constantly wishing that they will hopefully find their way back home to Vienna, well due to that, the two are casually accepting it, so they get it now.
And we'll continue on...
705.705.705.January meets a girlfriend
We're continuing where we had left off.
January and Anita are luckily getting reunited Sophie, Jocke, as well as many of January's friends and cousins. They're reunited together cause they're making it a pretty good teamwork. Well anyway, for some reason, Anita wonders what the gang will do today and answers her own question with "I dunno!" Just then, the door opens up, and from the door comes some brand new friends: Manni, Lola, Cy, Fly, and many more brand new friends. They join January's gang, so without further ado, we're about to introduce January and co..
And we'll continue on...
706.706.706.January encounters some friends, by joining them into January's gang
707.707.707.Introducing January and co.
708.708.708.January and co. begins their experience
709.709.709.January and co. gets their first start
710.710.710.January and co. gets a brand new start
711.711.711.January and co. begins a brand new day
712.712.712.January and co. opens up January's own career
713.713.713.January and co. trains their workout
714.714.714.January and co. gets ready to declare their hero-bravery of hero-braveness
715.715.715.January and co. smooths it up on training from bad mood to good mood, by making it fabulous from sad to fab
716.716.716.January and co. makes it hero-brave of becoming brave and bold
717.717.717.January and co. are ready to make it frenzy
718.718.718.January and co. are 1000% proud of boosting it up pretty good
719.719.719.January and co. upgrades their awesomeness
720.720.720.January and co. are ready to get going, and with that, they're ready to go for it
We're continuing where we had left off.
January and co. are always getting started, cause they're about to get their adventure started right now. Well eitherway, they're about to engage some funny signs.
And we'll continue on...
721.721.721.January and co. engages some funny signs
722.722.722.January and co. engages the son of some funny signs
723.723.723.January and co. engages the son of the son of funny signs
724.724.724.January and co. engages some more funny signs
725.725.725.January and co. engages still more funny signs
726.726.726.January and co. engages those further adventures of funny signs
727.727.727.January and co. joins into the fun of funny signs
728.728.728.January and co. gets into business with some funny signs
729.729.729.January and co. confronts an funny sign assurance
730.730.730.January and co. gets paid with some funny signs
731.731.731.January and co. gets some funny sign trouble
732.732.732.January and co. gets some more funny sign trouble
733.733.733.January and co. gets still more funny sign trouble
734.734.734.January and co. gets another more funny sign trouble
735.735.735.January and co. gets still another more funny sign trouble
736.736.736.January and co. gets yet another more funny sign trouble
737.737.737.January and co. gets still yet another more funny sign trouble
738.738.738.January and co. gets yet again another more funny sign trouble
739.739.739.January and co. gets still yet again another more funny sign trouble
740.740.740.January and co. gets those further adventures of funny sign trouble
741.741.741.January and co. gets an funny sign attitude
742.742.742.January and co. confesses the funny sign attitude
743.743.743.January and co. makes the funny sign get the wrong way
744.744.744.January and co. are accidentally advancing the wrong way with some funny signs
745.745.745.January and co. gets some party crashers with some funny signs
746.746.746.January and co. gets an funny sign catastrophe
747.747.747.January and co. does whatever they do, but they won't mess with those funny signs
748.748.748.January and co. does the most dumb, as they accidentally mess with those funny signs
749.749.749.January and co. takes cover of some fake funny signs
750.750.750.January and co. gets rushed by those fake funny signs
751.751.751.January and co. gets troubled by those party-crashing funny signs
752.752.752.January and co. gets jumpscared by those aggressive party-crashing funny signs
753.753.753.January and co. gets some funny sign chaos
754.754.754.January and co. gets some more funny sign chaos
755.755.755.January and co. engages an funny sign parody
756.756.756.January and co. confronts an annoying funny sign parody
757.757.757.January and co. engages an funny sign sequel
758.758.758.January and co. gets attacked by that dreaded funny sign sequel
759.759.759.January and co. gets misspelled with those funny signs
760.760.760.January and co. gets accidentally chained to those funny signs
761.761.761.January and co. gets the wrong funny sign mistake
762.762.762.January and co. picks up the wrong funny sign mistake
763.763.763.January and co. and the son of funny sign chaos
764.764.764.January and co. and the son of the son of funny sign chaos
765.765.765.January and co. engages another unnecessary funny sign sequel
766.766.766.January and co. engages yet another unnecessary funny sign sequel
767.767.767.January and co. gets another more funny sign chaos
768.768.768.January and co. gets yet another more funny sign chaos
769.769.769.January and co. gets get smacked off from those funny signs
770.770.770.January and co. gets banned by those funny signs
771.771.771.While January's away, the rest of his gang carries on, as the funny signs goes on
772.772.772.The funny signs still goes on, and then, January returns as he rejoins his gang
773.773.773.January and co. gets surrounded by those nasty funny sign bloopers
774.774.774.January and co. gets troubled by those notorious funny sign bloopers
775.775.775.January and co. gets some rogue funny sign boogaloo
776.776.776.January and co. bungles those funny signs
777.777.777.January and co. gets everything, but the funny signs
778.778.778.January and co. mentions the missing funny signs
779.779.779.January and co. gets the funny sign freedom
780.780.780.January and co. gets the funny sign liberty
781.781.781.January and co. engages yet again another more unnecessary funny sign sequel
782.782.782.January and co. engages yet once again another more unnecessary funny sign sequel
783.783.783.January and co. gets another funny sign invasion
784.784.784.January and co. gets yet another funny sign invasion
785.785.785."Uh oh, those crazy funny signs!"
786.786.786."Those funny signs are going crazy"
787.787.787.January and co. encounters some funny sign riders
788.788.788.January and co. races with those funny sign riders
789.789.789.January and co. engages some footprints from another error
790.790.790.January and co. investigates a mysterious funny sign bruise
791.791.791.January and co. requires an tough funny sign scheme
792.792.792.January and co. picks up some satisfying assembly of funny signs
793.793.793.January and co. and the close encounters of the funny sign kind
794.794.794.January and co. gets attacked by the invasion of the funny sign maniacs
795.795.795.January and co. goes to SMS-land
796.796.796.January and co. engages some crazy SMS's
797.797.797.January and co. plays games with those funny signs
798.798.798.January and co. harvests with those funny signs
799.799.799.January and co. gets pursued by the return of those mangled, tangled and discombobulated funny signs
800.800.800.January and co. gets attacked by those mangy, dreaded and selfish funny signs
801.801.801.January and co. gets some funny sign mayhem
802.802.802.January and co. gets sucked into a mayhem of funny signs
803.803.803.January and co. loses control with those funny signs
804.804.804.January and co. goes out of control with those funny signs
805.805.805.January and co. gets some funny sign fever
806.806.806.January and co. gets some funny sign donk-donk
807.807.807.January and co. and the funny sign unmasked
...
We'll be right back after the break...
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Już po prześwietleniu. MRI - to jak lot kosmiczny. Pan radiolog pewnie słyszał tą wypowiedz setki razy. Cholernie dziwne uczucie wjeżdżając do środka tuby w majtkach, skarpetkach i koszulce. 10 minut. Zamknąłem oczy w słuchawkach jedna z popowych stacji NRK, z radosna muzyka, bo przecież dziś piątek i Norwegowie mogą szybciej wyjść z biura. „Tylko sie nie ruszaj, bo obraz będzie zamazany”. Mając to w myślach, próbuje sie nie ruszać, choć czuje jak lekko drżą mi nogi. W głowie mętlik, bo przecież overthink.
Sam nie wiem czego oczekiwać. Trzeba czekać 6 dni roboczych na wyniki. Później do lekarza pierwszego kontaktu, na analizę wyników i werdykt odnośnie mojego zdrowia.
Cold brew - typ kawy, który pije dla przyjemności. Chodzę szukam i chyba nigdzie oprócz Starbucksa nie ma. Zamówiłem americano z lodem, okazało się, ze maszyna z kostkami lodu nie działa. Cóż. Kawa czarna jak moja dusza i w dodatku gorąca. Lubie kawę w temperaturze, w której mogę ja wypić duszkiem gdy zechce.
Oslo stolica, a sklepy do których próbuje się dostać otwarte od 10.
Edit : 16:19
Krzatalem sie po okolicy, najpierw do azjatyckiego, pozniej do bliskowschodniego sklepu po peczek koledry i miety. W drodze powrotnej na tramwaj wskoczylem jeszcze do sklepu ze zdrowo zywnoscia, w ktorym mozna dostac tortille z kukurydzy i inne rzeczy produkcji meksykanskiej. Zwarzywszy, ze dzis piatek, a w Norwegi w piatki jada sie taco, jak w niedziele w polsce rosol. Przy polkach zaczepil mnie chlopak na oko w moim wieku moze troche mlodszy, musialem zdjac sluchawki. Okazalo sie, ze byl z wyzej wspomnianego NRK i chcial ze mna zrobic wywiad o zakupach meksykanskich prodoktow. Zgodzilem sie, ale nie sadze, zeby mnie gdzies wrzucil, bo zaskoczyl mnie potwornie i moj norweski improwizowany, w sytuacjach w ktorych nie jestem przygotowany do rozmowy nie wypada najlepiej. Coz... Zreszta jakie to ma znaczenie i kogo to interesuje.
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youtube
Play again Wednesday episode, Freestyle Funk Selection 2 hours. Selected tunes from wide range of type of music totally funky.
Listen and enjoy and check tunes !
1. "Time" STUFF N' RAMJETT (Chelsea)
2. "This Time" FAMILY CONNECTION (Jabali)
3. "Makeup Lovin"GUYMAN ENSLEY (Cordial Recordings)
4. "Check Out Your Mind" THE IMPRESSIONS (Curtom)
5. "Wind It Up" BOBBY WOMACK (Columbia)
6. "You've Lost That Lovin' Feelin'" MARTHA REEVES (Arista)
7. "Happy Feelin'" EARTH, WIND AND FIRE (Columbia)
8. "Keep That Same Old Feeling" SIDE EFFECT (Fantasy)
9. "I Know I'm Falling In Love" CHANTIQUE (AIP International)
10. "Who Do You Love" JOHN SIMEONE (TNT)
11. "Mercury" STEVE LACY (RCA)
12. "Love Comes Easy" THE SACRED SOULS (Daptone)
13. "Sea Of Love" DURAND JONES & THE INDICATIONS (Colemine)
14. "Jos Vois" AARON (Traveller)
15. "Turn It Up" THE BAMBOOS feat LYRICS BORN (Tru Thoughts)
16. "Sir Racha" LYRICS BORN (Mobile Home)
17. "Hot Pants" THE BAND NO NAME (NRK)
18. ”Groovy World" FABULOUS CAPRICES (Camaro)
19. "Super Dynamite" CHORDATA (Preservation Project)
20. "Look At My Back Wheels" THE MICHIGANS (Tumbleweed)
21. "Soulful Trip" ERNIE HAWKS & THE SOUL IG'S (Nite Club)
22. "Crawdad Hole aka Crawdad Song" THE DENVER AFFAIR (Contempo)
23. "All Africa" MELANIE CHARLES (Verve)
24. "Carpet Ride" JAMBONNE (Space Grapes)
25. "Starlight" DAVE & OMAR (ZR)
26. "Est-Ce Que C'est Chic" CHIC (Atlantic)
27. "Let's Go Dance Tonight" LAMONT JOHNSON & EUGENE (Soul Junction)
28. "Space Walking" MAGGABRAIN (Cordial Recordnings)
29. "Share Your Love" HERMAN KELLY & LIFE (RCA)
30. "It's Alright (This Feeling)" CRACK OF DAWN (Columbia)
31. "Til I Met Thee" CODY CHESNUTT (One Little Indian)
32. "Tied Up" THE NORTHERN LIGHTS (Traveller)
33. "Show Is Over" GATEWAY (Super Disco Edits)
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I posted 123 times in 2022
That's 83 more posts than 2021!
16 posts created (13%)
107 posts reblogged (87%)
Blogs I reblogged the most:
@the-skeletoninyour-closet
@beradan
@renee-niles
@silversouledcat
@jadewing
I tagged 111 of my posts in 2022
Only 10% of my posts had no tags
#my life - 25 posts
#college life - 11 posts
#ask - 7 posts
#follow the side blog - 7 posts
#tumblr paper - 5 posts
#ask post - 4 posts
#book - 4 posts
#tumblr - 4 posts
#yes this - 4 posts
#art - 3 posts
Longest Tag: 137 characters
#and when our trip returned we had to awkwardly wait for a bit in the parking lot while they decided if they would let us enter the school
My Top Posts in 2022:
#5
What is your favorite memory about a book?
Oh, so many I can pick from... hard to choose a favorite, but here's one of the first happy ones that came to mind. This isn't about the content of a book, but about an interaction related to one.
When I was in eighth grade (thirteen years old, for those non-Americans out there), I loved Rick Riordan's books. At the time, the Heroes of Olympus series was being released, and I'd just gotten a copy of the newest book - I think Mark of Athena? I forget which one it was. I still enjoy Riordan's writing, though I prefer his Norse and Egyptian books over the Greek/Roman crossover that was Heroes of Olympus.
I finished reading my copy of the book decently quickly, and a friend of mine one grade above me (ninth grade/freshman year, first year of high school) asked if he could borrow it. I said yes, wrote my name inside, and made him promise to take care of it.
A few weeks later, I went to see the high school's production of You're A Good Man, Charlie Brown. My friend was in the ensemble, and the director had the ensemble doing various things in the background of some of the scenes while staying on stage.
My friend was reading my book, onstage!
MY book!
It almost felt like I was onstage too, since something I owned was. Alas, I didn't make my debut onstage until the next year since they only allowed high schoolers to audition.
2 notes - Posted July 18, 2022
#4
I’m listening to the music of @reallyndacarter while writing the final essay for one of my grad school classes.
Once I finish this paper, I think I’ll add at least a few of these songs to some of my playlists.
3 notes - Posted December 6, 2022
#3
youtube
Guys... BDG made a video on how American health insurance works.
It’s both informative and a meme at the same time.
3 notes - Posted September 26, 2022
#2
I came across this video while doing homework for a grad school class...
oh boy does this bring back memories from when I used to work in IT.
6 notes - Posted August 21, 2022
My #1 post of 2022
Are you willing to elaborate on your current job(s)?
Not publicly, no.
All I'll say is that I'm managing a small library while working towards my masters in library science.
14 notes - Posted November 16, 2022
Get your Tumblr 2022 Year in Review →
#tumblr2022#year in review#my 2022 tumblr year in review#your tumblr year in review#yup I don't post much stuff that isn't reblogs#that's just how it be#Youtube
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A Ludvig Holberg
Johan Halvorsen (1864 - 4 dicembre 1935): Suite ancienne per orchestra op. 31 (1911), in memoria di Ludvig Holberg. Orchestra della Radio norvegese (NRK, Norsk rikskringkasting), dir. Ari Rasilainen.
Intrata
Air con variazioni [5:21]
Gigue [16:12]
Sarabande [20:52]
Bourrée [24:42]
Edvard Grieg (1843 - 1907): Fra Holbergs tid (Dai tempi di Holberg), suite op. 40, versione per orchestra d’archi…
View On WordPress
#Ari Rasilainen#Camerata Nordica#Edvard Grieg#Jørgen Roed#Johan Halvorsen#Ludvig Holberg#Orchestra della Radio norvegese#Terje Tønnesen
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Biomed Grid | The Role of NAD+ in Anti-Aging Therapies
Introduction
The aging process is influenced by a variety of factors and considered to be an irreversible process. Aging of an organism is accompanied by metabolic disorders and the impairment of physiological function, as well as the development of age-related diseases [1, 2, [3, 4]. There is abundant evidence that NAD+ plays an important role in aging, as it is involved in various biological functions and is a key regulator of stress resistance [5, 6]. Levels of NAD+ steadily decline with age, resulting in altered metabolism and increased disease susceptibility [7, 8, 9]. NAD+ plays a key role in various energy metabolism pathways [6, 10]. Additionally, NAD+ is a cofactor for many enzymes, such as poly (ADP-ribose) polymerases (PARPs), CD38, and sirtuins [11]. Sirtuins are NAD+-dependent histone deacetylase for a wide range of transcriptional regulators [10, 12]. Overexpression of SIRT1 in the brains of mice has been shown to delay aging [13]. PARP is a major NAD+-degrading enzyme, which plays diverse roles in many molecular and cellular processes [14]. Inhibition of PARP-1 increases mitochondrial metabolism via modulation of SIRT1 activity [15]. Another NAD+-degrading enzyme, CD38, had been associated with the decline in NAD+ levels during aging [16].
Mammalian cells cannot import NAD+ in vivo, so they must synthesize it either from tryptophan or the various forms of niacin taken up in the diet including nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) [17, 18, 19, 20]. Recently, it was found in mice that supplementing with NAD+ precursors (including NMN, NR, and nicotinamide) or inhibiting the activity of NAD+-consuming enzymes can increase the level of NAD+ in tissues and improve energy metabolism, thereby delaying aging and extending healthy life [15, 21, [22, 23, 24].
Currently, the anti-aging activity of NAD+ precursors is primarily evaluated through measurement of aging markers in mouse behavior, accumulation of DNA damage, and mitochondrial activity. RNA sequencing has also been used to identify genes and pathways involved in the anti-aging mechanisms of NAD+ [20, 22, [25, 4]. Furthermore, recent research has shown that biological age can be measured by analyzing the 353 DNA methylation sites of the Horvath clock [30, 31].
NAD
+
Biosynthesis-Salvage Pathway
In vivo, NAD+ is an essential cofactor of dehydrogenase [32, 33].Nicotinamide coenzyme is an electron carrier which plays an important role in various oxidation-reduction reactions. Therefore NAD+ is a cofactor of many key enzymes in glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation [34]. Age-associated decline in NAD+ availability has an important effect on the aging process of many species [8, 35, 36]. There are three pathways for the synthesis of NAD+ in cells, involving many different precursors [37, 38, 39]. Here we focus on the salvage pathway, which is important from a translational research perspective because it is the main source of NAD+ [40, 41].
There are three pathways for the synthesis of NAD+ in cells:
a. de novo from tryptophan;
b. from nicotinic acid via the Preiss-Handler pathway; and
c. from nicotinamide (NAM) via the salvage pathway [37].
NAM itself is a by-product of NAD+-degrading enzymes such as sirtuins and PARP. As shown in (Figure 1) , the first step of the salvage pathway is catalyzed by nicotinamide phosphoribosyl-transferase (NAMPT), which converts nicotinamide and 5-phosphoribosyl- 1-pyrophosphate into NMN [42]. Subsequently, nicotinamide mononucleotide adenylyltransferase (NMNAT) produces NAD+ from NMN and ATP [43, 44]. NR can be converted by nicotinamideriboside kinase (NRK) into NMN which participating in the Salvage pathway [45]. NAMPT is the rate-limiting enzyme of the salvage pathway [42]. It has been hypothesized that reduced NAD+ synthesis is one of the causes of lower NAD+ levels with aging, and this may be due to decreased activity of NAMPT [42, 46]. Indeed, NAMPT levels are known to decline with age in many types of tissues [47, 48, 49], whereas exercise increases skeletal muscle NAMPT expression [50].
Figure 1: The Salvage pathway NAM and NR are the main precursor for the salvage pathway.
In mammals, NAMPT has two different forms: intra- and extracellular [51]. The intracellular form is the one that participates in the salvage pathway of NAD+ synthesis [42], while the extracellular form likely functions as a circulating cytokine [52]. Studies have shown that secretion of NAMPT is regulated by SIRT1 in vivo [53, 4], and SIRT1 activity in turn depends on NAMPT which regulates level of NAD+ [54]. Increasing level of NAMPT may delay aging of individuals via SIRT1-dependent pathways [56]. NAMPT has been shown to regulate osteoblast differentiation in primary culture of mouse bone marrow-derived mesenchymal stem cells via NAD+-SIRT1 pathway. NAMPT deficiency may increase the risk of bone aging or fractures [48, 57, [58, 59].
Levels of NAMPT significantly decrease with age in mice and humans [60, 61]. Adipose tissue-specific overexpression of NAMPT in aged mice resulted in increased levels of circulating eNAMPT, increased levels of NAD+ in multiple tissues, and extended lifespan [60].
In mammals NMNAT is the central enzyme of the NAD biosynthetic pathway [43,62]. There are three isoforms, NMNAT1, NMNAT2, and NMNAT3, encoded by different genes and localized to nucleus, Golgi apparatus, and mitochondria, respectively [43]. NMNAT1 directly control SIRT1 deacetylase activity at a set of target gene promoters [63]. Homozygous knockout of Nmnat1 in mice results in embryonic death [64]. Low levels of NMNAT2, highly expressed in the brain and nervous system, could impair axon regeneration as well as axon survival in aging and disease [65,66]. NMNAT3 has been identified as the rate-limiting enzyme for mitochondrial NAD+ biosynthesis [67]. In addition, down-regulation of NMNAT3 gene expression in cells significantly impairs the capacity for mitochondrial respiration, suggesting that NMNAT3 plays a key role in mitochondrial NAD+ homeostasis [68].
Anti-aging effects of NAD
+
Through its role as a substrate for sirtuins, CD38, and PARP, NAD+ regulates a variety of cellular process including energy metabolism, DNA damage repair, gene expression, and oxidative stress response [11, 34, 69, 70].
a. The Sirtuins Pathway
Sirtuins are evolutionarily conserved NAD+-dependent deacetylases. Increasing sirtuin expression has been shown to affect lifes< pan across various species [13, 36, [71, 72]. Sirtuins have received significant attention since the discovery that the increased sirtuin silent information regulator 2 (Sir2) can extend yeast lifespan [72]. The closest mammalian homologue of this regulator is SIRT1[69], mainly localized in the nucleus but also present in cytosol [73]. Its nuclear export signal allows shuttling to the cytosol under specific circumstance [12]. It has been shown in vivo that NAD+-SIRT1 signaling promotes mitochondrial activity [25]. Previous research has suggested that increasing SIRT1 in the brain, especially in the dorsomedial and lateral hypothalamic nuclei, can delay aging and extend lifespan in mice [13]. More recently, heart-specific overexpression of Sirt1 was found to delay aging and protect against oxidative stress in the heart [74]. NR-SIRT1 signaling can inhibit cardiac stem cell senescence by improving mitochondrial function and muscle stem cell function, thereby enhancing life span in mice [25]. More research is needed to determine whether increased level of NAD+ in vivo can improve SIRT1 activity, thereby delaying aging [75].
b. The PARPs Pathway
PARPs are expressed by most eukaryotic cells and are involved in DNA damage detection and repair, cell death pathways and so on [14]. Aging is associated with an accumulation of DNA damage [76]. Depletion of NAD+ is involved in cell death through PARP-1 [70]. Although this enzyme plays an important role in cells, over-activation of PARP-1 can lead to depletion of NAD+, reduction of ATP, reducing the activity of SIRT1, loss of mitochondrial function, and even cell death [70, 77, 78]. Increased level of NAD+, when SIRT1 is intact, can reduce the cell death caused by activation of PARP-1 in cardiac myocyte [79].
c. CD38 and NAD
+
CD38 is a multi-functional protein. Studies have shown that CD38 is the NADase in mammalian tissues [80, 81, 4]. It is thought to contribute to the age-related decline in NAD+ levels [23, 80, 82]. CD38 also acts as an antigen for B-lymphocyte activation and as an ecto-enzyme in endothelial and inflammatory cells [82, 83, 4]. Senescent cells are known to express small molecules including secreted cytokines, growth factors, and extracellular matrix modifiers to promote chronic sterile inflammation and fibrosis. This reaction process, known as the senescence-associated secretory phenotype [84, 85, 86], involves secretion of factors by senescent cells which induce the expression of CD38 in non-senescent cells [82, 87,]. This increased CD38 activity can disrupt the fine balance between NAD+ and its reduced form, NADH, within a cell [82]. Recently, the small molecule CD38 inhibitor 78c was shown to reverse the age-related loss of NAD+ [28, 83,]. By increasing tissue levels of NAD+, 78c may be able to ameliorate metabolic disorder and other disruptions involved in the aging process. In addition, animals treated with 78c show activation of longevity genes, which inhibit DNA damage [28].
NAD+ and NADH are in dynamic equilibrium within the cell [75]. Intracellular NAD+ can be increased in vivo through oral administration of NAD+ precursor or by inhibiting the degradation of NAD+ [15, 23, 88]. Regulation of the NAD+/ NADH ratio in this way can improve mitochondrial function and has been shown to treat senile deafness in elderly mice [89].
NAD
+
Repletion and Aging
One of the major causes of aging is progressive tissue degeneration and atrophy due to reduced somatic or stem cell function [22,90,91]. Adult stem cells are not only essential in continuously proliferating tissues (such as hematopoietic, intestinal, and skin systems) but also in normally quiescent tissues (such as skeletal muscle and the brain) that require regeneration after damage or exposure to disease [92]. NR supplementation improved metabolic function in muscle and neural stem cells, in both young and old mice, thereby increasing lifespan [25]. NR treatment has also been shown to rejuvenate stem cells from aged mice and restore the impaired ability to repair gut damage [22]. Previous studies have shown that DNA damage of nerve cells, nerve stem cells, and muscle stem cells in mice can be reduced by NR supplementation [25, 93]. NR has also been shown to ameliorate mitochondrial dysfunction and enhance oxidative metabolism in obese mice [94, 95] and prolong the lifespan of mice through neuronal DNA repair and mitochondrial quality improvement [96, 97].
Supplementation with NMN can restore age-related capillary rarefaction and increase blood flow in elderly mice, and it maybe a novel therapy to restore SIRT1 activity and reverse age-related arterial dysfunction by reducing oxidative stress [98, 99]. Mitochondrial disorders due to impaired oxidative phosphorylation (OXPHOS) are a cause of aging [100]. Long-term treatment with NMN in elderly C57BL/6J mice can improve metabolic dysfunction and ameliorate age-associated physiological decline [20]. NMN can also restore mitochondrial function, prevent neural death, and delay cognitive decline in a mouse model of Alzheimer’s disease [101, 102]. Supplementation with NAM was shown to improve blood sugar levels and metabolic capacity in HFD-fed mice. However, it had no effect on lifespan [103].
There are data showing that supplementation with NAD+ precursors enhanced the mitochondrial function of cells or stem cells in a SIRT1-dependent manner [25, 94]. Furthermore, supplementing NAD+ precursors in elderly mice improved mitochondrial function in hematopoietic stem cells and muscle stem cells, as well as extended lifespan [25, 104]. NMN specifically was found to enhance the biological activity of mesenchymal stromal cells through the upregulation of SIRT1, thereby stimulating osteogenesis of the cells and protecting bone from aging to delay the aging of mice [105]. In elderly mice, NMN treatment improved capillary density through the NAD+-H2S signaling network to increase blood flow, endurance, and physiological status [27, 29, 106].
Inhibition of some NAD+-degrading enzymes could also lead to increased levels of NAD+ [15, 23]. CD38, PARPs, and SARM1 all degrade NAD+ inside the cell [23, 77, [80, 107]. The activity of CD38 increases with aging, contributing to the age-related decline in NAD+ [16]. Several small-molecule inhibitors of CD38 have been described [83, 108, [109, 110]. Thiazoloquin(az)olin(on)e is one such inhibitor which could potentially be used as a therapeutic agent to increase intracellular NAD+ level [28]. Inhibition of PARP1 has recently been reported to correct mitochondrial impairment [111, 112] and has strong metabolic implications through its modulation of SIRT1 activity [15].
Measure Biological Age
Thus far, the anti-aging activity of NAD+ is mainly examined using RNA sequencing and gene set enrichment analysis to identify pathways of candidate biomarkers [20, 22, 25]. However, there is not yet a gold standard for aging biomarkers. The DNA clock may offer a better objective biomarker for the study of aging [30, 31]. DNA methylation plays a critical role in the regulation of gene transcription [113, 114, 115, 116, 117, 118]. Senescence can be predicted and evaluated by detecting cytosine-5 methylation within CpG dinucleotides [30, 31]. These age-related CpG characteristics are independent of gender or tissue type. Recent research has shown that biological age can be approximated by measuring levels of DNA methylation, a process known as the Horvath (or DNA) clock [30, 31, [119, 120]. Age-related DNA methylation was first described for humans after cross comparison of thousands of CpG sites in Illumina Bead Chip microarray data [121, 122]. Many of these age-associated CpG sites were then used as epigenetic age-predictors [30, 31, [120, 123]. Three hundred and fifty-three unique CpG sites were found to be predictive of biological age, independent of chromatin status or tissue source [30, 31].
Petkovich et al. developed a robust predictor of mouse biological age based on 90 CpG sites derived from partial blood DNA methylation profiles [124]. Stubbs et al. further developed a multi-tissue predictor to estimate age based on DNA methylation at 329 unique CpG sites from various different mouse tissues [125]. One group claims to have found three methylation sites, Prima1, Hsf4, and Kcns1, which are enough to predict biological age in mice [126]. However, this study has yet to be replicated. The most accurate clock results from applying elastic net regression to all CpGs for multi-tissue in mice [127].
Together these studies suggest that the DNA clock provides an objective biomarker for the study of aging [30, 31]. Recently, metformin has shown that reversed subject’s biological age, based on assessment of Horvath clock [128, 129]. Its use will allow us to examine the anti-aging effectiveness of NAD+ and its precursors more objectively and accurately.
Clinical Research
NAD+ precursors can be delivered orally to humans or animals to alter the dynamic balance of NAD+/NADH in vivo [24, 130]. Preliminary clinical studies in humans showed that NR supplementation could improve muscle NAD+ metabolism in the elderly [131, 132]. Healthy volunteers, who underwent an 8-day course of NR, with doses increasing from 250 mg to 1000 mg, showed increased levels of circulating NAD+ and experienced no adverse side effects [133]. Similarly, NR supplementation increased NADH and NADPH levels and improved exercise performance in elderly subjects [134]. Therefore, NMN is considered safe in clinical trials [135]. However, high dose supplementation with NAD+ precursors may increase rates of glycolysis and mitochondrial respiratory metabolism, thereby promoting the secretion of proinflammatory cytokines in cells [136]. Thus, use of supplements should be carefully observed to ensure that they strike a proper balance between anti- aging effects and potential detrimental effects.
Conclusion
NAD+ is a cofactor for many important enzymes. Reduced levels of NAD+ have been associated with aging. Evidence suggests that supplementation with NAD+ precursors, or inhibition of NAD+ degradation, could improve metabolic function. While supplementation with NAD+ precursors has been found to delay aging in mice, anti-aging effects of NAD+ have yet to be demonstrated in human subjects. Use of a more accurate biomarker for aging, such as the DNA methylation clock, will significantly advance the field. Recently, several human clinical trials have been initiated.
Read More About this Article: https://biomedgrid.com/fulltext/volume6/the-role-of-nad-in-anti-aging-therapies.001080.php
For more about: Journals on Biomedical Science :Biomed Grid | Current Issue
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