With regular host Matt Egan off ill, David Price steps in to discuss Microsoft Teams, the government's 'new' cyber security strategy and the collision of social media and insurance companies. First up, producer Chris is on to discuss Microsoft's recent Slack rival Microsoft Teams and wether it can win the market. Then Scott Carey, online editor at Computerworld UK, talks about the government's newest strategy for taking on cyber crime. Then Charlotte Jee, editor of Techworld, talks about UK insurer Admiral's misjudged attempt to use Facebook posts to offer discounts on insurance premiums.  

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Host Matt Egan is in a sombre mood this week as the tech industry comes to terms with a Donald Trump US presidency. Staff writer at Macworld UK dives into what this could mean for Silicon Valley, Apple products and wether social media is at fault. Then producer Chris comes on to discuss the latest addition to the VR headset market with Google's Daydream. Will it be held back by a lack of applications though? (14:45) Finally, online editor at Computerworld UK talks about the biggest data breach at a UK bank, as Tesco Bank suffers a £2.5 million cyber theft and what this means for the banking industry as a whole (25:00).  

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Join host David Price for a dive into all things tech: Round 43. Things go mobile as Senior Staff Writer at PC Advisor and Macworld UK Henry Burrell tells us why Sky getting into the market is a big deal. Quad-play ahoy. Then fellow Senior Staff Writer Lewis Painter (14 mins) tells us why No Man's Sky is still making the headlines, this time for making stuff up. How far have companies taken false advertising in recent years? Third up is Techworld editor Charlotte Jee (25 mins) to talk about how the government has perhaps avoided taking responsibility when it comes to sex-ed and instead suggested it ban sexting - is that even possible? Listen on to find out.  

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This week Henry Burrell is in the presenter chair and he has brought puns, sing-songs and tenuous Field of Dreams references. First up is producer Chris to discuss the Fitbit acquisition of fellow wearable maker Pebble and why owners are sad. Then online editor at Techworld Tamlin Magee is discussing the Met Police's decision to upload their body camera footage to the cloud and why this could be problematic (12:00). Finally, fellow online editor Scott Carey runs us through the Amazon Go news and how the retail giant is trying to pull off the technology behind its 'just walk out' shopping experience (24:00).  

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Host Henry Burrell leads the team into a tangle of nitty gritty tech topics in the penultimate pod of the year. Macworld UK Acting Editor David Price tells us why Apple and Nintendo very nearly scored a home run with Super Mario Run, but just missed out. The team, led by Charlotte Jee, Editor of Techworld then tackle Amazon's latest endeavour to solve first world problems (provided you live in Cambridge) (13 mins). Tamlin Magee, Online Editor at Techworld then leads us onto the sticky topic of defining extreme terror online and which big companies have a responsibility to police the Internet (27 mins).  

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This week David Price is in the presenter chair for the jolliest tech podcast of the year. David is joined by Miriam Harris, staff writer at Digital Arts, to talk about the design trends set to shape 2017. Then online editor at Techworld Scott Carey runs through the hottest tech gifts this Christmas, including games consoles, VR, Amazon gadgets and Star Wars merch (14:30). Finally, staff writer at PC Advisor Dom Preston makes his UKTW debut to chat about the latest Star Wars movie, Rogue One, which includes spoilers (29:00). This is the last UK Tech Weekly podcast of the year. Thank you for listening and we will be back in 2017 to chat about the hottest tech topics all over again.  

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Host Matt Egan clips us round the ear and tells us to listen up as we chat yet more tech and then some other stuff about tech. Consumer tech editor at PC Advisor Chris Martin lays down his definitive opinion after he went hands on with the Nintendo Switch this week, and why the company really should have had their star plumber ready in time for launch. Tamlin Magee, Online Editor at Computerworld UK then takes us through the odd goings on at Davos, and whether or not the elite can identify with what tech actually means to real working people. To round us up, Acting Macworld UK Editor David Price explains why app prices are going up in the UK for iOS users, and why it might - might - not be UKIP's fault. Sort of.  

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Matt Egan hosts as we delve into the tech headlines of the week. Senior Staff Writer at PC Advisor Henry Burrell talks the gang through the latest on Samsung's upcoming smartphone and why it's been delayed, plus another brand comes back from the brink. Online Editor at Techworld Tamlin Magee then explores the strange but true story of Silicon Valley billionaires buying private islands with underground bunkers in case everything really does go Pete Tong. Finally Staff Writer at Macworld UK and PC Advisor Dominic Preston talks us through the frights of the latest Resident Evil game while everyone agrees they can be more terrifying than most horror films.  

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Matt Egan takes us where no other pod has dared gone before (September 2000) and asks Digital Arts Editor Neil Bennett if anyone cares that Nokia is rereleasing the famous 3310. Is it cool to rock one now? Then Techworld Audience Development Editor Christina Mercer lets us know that the future is already here with self driving drone taxis. Would you hitch a lift round Dubai on a massive quadcopter? Finally Deputy Editor at Macworld David Price ruminates on Apple's forecast foray into the world of snackable media content - will it challenge Netflix or try to buy it?  

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Allow Matt Egan (and Shed7) to lull you into this week's pod as we tackle the big tech issues of the week. Staff Writer at Digital Arts Miriam Harris explains the latest HR and PR mess over at Uber. How long will consumers use a service when the company are clearly not treating its staff well? Then (16:30) Deputy Editor of Macworld UK David Price gets excited about Apple Park, the so-called 'spaceship campus' that has been under construction for years. May contain orchards. Finally (26:48) Senior Staff Writer at Tech Advisor Henry Burrell previews Mobile World Congress which gets underway on 26th February. Are any of the major handset launches worth your attention?  

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Host Matt Egan leads a three pronged tech attack on the week's news with David Price and Scott Carey. The gang discuss 'BBC Dad' and why the professor's hilarious children are the perfect example of viral video. David Price also examines the news cycle of such treats, and why ambulance drivers aren't on Twitter all the time. With Marissa Mayer leaving Yahoo! in tatters, renamed, but with a wad of cash reportedly in her account, Scott leads the line in exploring where it went wrong and why it has been such a public fall from grace. But at age 41, surely there's another chapter in Mayer's story?  

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Gather round as three men spend 30 minutes talking about tech. Wait, what do you mean 'no thanks'?! Matt Egan shares the mic with David Price and Henry Burrell to thrash out why Apple deemed a press release adequate to announce the successor to 2014's iPad Air 2. There's also a slick new red iPhone, and a black OnePlus 3T. What's with the limited editions, eh? Or are they even limited? The gang also chat about the developer preview of Android O, out now while Android N is barely months old. Is it too early to say if it'll kick ass, and why do Google and Apple need such long public lead time with new OS builds?  

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David Price leads the line this week to see how Samsung's Galaxy S8 came out fighting in London and New York this week. It's blown up! But not like that. Had to get that joke (poorly) out of the way. Chris Martin tells all. Then (18 mins) Cam Mitchell takes aim at Home Secretary Amber Rudd's ill advised comments on encryption and wanting government backdoor access to WhatsApp. Does her basic misunderstanding of privacy rights and how tech works extend to the wider population? And then Dom Preston (31 mins) tells us why Hollywood gone and done another flop, and why Ghost in the Shell is a red (or Scarlett!!!!!) mark against remakes.  

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Join host Henry Burrell in conversation with two editors, Karen Khan of Macworld UK in her debut pod along with pod regular Charlotte Jee of Techworld. We tackle the issues of privacy and self esteem, particularly in the young people that we are not, and ask who this product is for (because surely it will sell). Tech obviously plays a big part in the selfie phenomenon/epidemic. Second we discuss automation and how it is affecting the job market. Can a robot make an iPhone? Is Trump right about bringin' it all back home? What should politicians be doing to understand the technology involved? Thanks for listening, listener.  

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We return like a nerdy phoenix for episode 66, where Henry Burrell leads David Price and Dominic Preston down the tech rabbit hole to discuss the week's news. Amazon Prime Day came and went, but what does it really mean for consumers and the media? Did you buy anything? Did you need it? The team then discuss the odd ongoing story of the man who lost copyright of an image of a monkey to... the monkey that allegedly took it. PETA got involved. It's weird. It's good to be back.  

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A classic edition of the pod as we hark back to the hallowed three topic format. Henry Burrell hosts David Price, Scott Carey and Chris Martin to ask just how Netflix got so popular. Will it sustain it though? Windows Phone is also pretty much actually dead but the funeral march is long. Other phone stuff includes the hallowed iPhone 8, the demise of Vertu and Nokia not really being Nokia. David then tells us why Google Glass is back, what it means for the enterprise, and why didn't they realise the first time round that it wasn't a consumer play?  

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Join Miriam Harris, David Price and Henry Burrell as they dissect the weird internal memo row at Google. Was a male engineer genuinely trying to help Google and make a point about the company being too Left, or is he just an arsehole? Then we describe the iPhone 8 dummy we received this week (take a look at it here: https://www.youtube.com/watch?v=PRNIwh61j_E ) and the revelations that came from the Homepod firmware leak. We also debate the usefulness of an LTE Apple Watch and try to make puns work. Magic.  

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Scott Carey necessarily tries to get his pronunciation game on fleek to deliver the latest Uber news - there's a new CEO in town, and it isn't a woman. Should it have been? He tells Henry Burrell what's next for the company. Then roles are reversed as Henry updates Scott on the Galaxy Note 8, LG V30 and September 12's very own iPhone 8 - will it be called that? Will anyone spend £1,000 on it?  

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This week it is all about Apple as the company announces its eagerly awaited iPhone X and iPhone 8/8 Plus smartphones, a new Apple watch (yawn) and Apple TV news. Macworld UK editor Karen Haslam is our host this week, as she chats to a distinctly unconvinced Dominic Preston about the latest iPhone, followed by David Price on the Apple Watch Series 3, which he likes but not as much as its predecessor. Then everyone piles in together to discuss the quite-good iPhone 8, the quite-late Apple TV 4K, and all the rest of the evening's festivities.  

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We back. Google and Amazon introduced a raft of new products for us to drool over and, of course, apply a degree of scepticism. Jim Martin was on the ground to use all the new Google stuff and has the latest. Scott then talks us through Uber's mishaps, this time its London licence has been revoked. Will the company go public when it wants to? Finally we discuss the SNES Mini which we managed to get our hands on and why Nintendo has such low stock of all its great products.  

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After a lengthy hiatus we are back to FINALLY talk about the iPhone X. Computerworld UK editor Scott Carey is in the hosting chair to chat with Chris Martin, reviews editor at Tech Advisor and Macworld UK, now that we have got our hands on one. Chris talks us through what he likes and dislikes so far about the pricey smartphone.

Then Miriam Harris, staff writer at Digital Arts jumps in to discuss the design principles behind driverless cars and what we can expect in the future (17:00).

Finally, pod debutante Caroline Vanier, senior staff writer at Tech Advisor France talks about the FairPhone and if it is a new model for the smart phone industry (28:00).

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2018 lands with a distinct thud as Charlotte Jee tackles Meltdown and Spectre, David Price wrestles with Apple's batteries and its new iMac Pro, before Miriam Harris works through the Bafta nominations for visual effects. Henry Burrell leads us down the rabbit hole.

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This week host Charlotte Jee breaks down open banking with Computerworld UK editor Scott Carey: what is it and why should we care?

Then audience development editor Christina Mercer explains why chip-maker Qualcomm has been fined nearly €1 billion and the EU's sustained attack on big tech (12:00)

Last up is senior staff writer at Tech Advisor Dom Preston to talk about Amazon's revolutionary concept Go store opening in Seattle and if this is really the future of shopping (20:00).

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Back with a bang as Computerworld editor Scott Carey leads the squad into the cauldron of convo. Christina Mercer explains why her beau Elon Musk took a car into space, Sean Bradley on that bursting Bitcoin bubble, and David Price to tell us all how Apple can charge even more for its stuff and keep on making record profit.

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We let one huge, scary story dominate proceedings before allowing two lighter-weight topics return the pod to its family friendly roots.

The Cambridge Analytica and Facebook scandal is decoded and discussed, with one podder especially susceptible to influence thanks to their insane third party app access numbers.

The gang then tackles Sea of Thieves, a return to form for Rare on Xbox, before Dom (with no spoilers) says just how bad Ready Player One is.

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Sheriff Scott Carey rounds up his two deputies in David Price and Henry Burrell for a quick-fire two topic pod. Apple launched a new cheaper iPad this week based around its education play - but can schools afford them and are Chromebooks a better option?

Then we discuss the new Huawei P20 and P20 Pro. Notches, three cameras but competitive pricing make the new Android flagship an interesting option.

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Back once again like the Renegade Master, the UK Tech Weekly Podcast is coming to you from its new, earlier-in-the-week time slot.

Host Scott Carey is joined by Tamlin Magee to talk about pirate-obsessed Nigerian hacking syndicates, and Charlotte Jee is on board to discuss the ethics of facial (and racial) recognition technology.

We wrap things up with an Elon Musk news roundup, from his latest bae to building bricks.

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With Germany out of the World Cup what better way to celebrate than with a triptych of tech news'n'views? Henry Burrell hears from Scott Carey on Uber's London license while Sean Bradley explains why Facebook banned, and then allowed, cryptocurrency ads.

Henry then shows off the new BlackBerry and a collection of other phones that Scott finds insulting and ridiculous.

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Join host Henry Burrell in hot as hell London town to bring you 40 minutes of air conditioned tech chat.

Tamlin Magee talks us through the murky ways IBM helped the Third Reich in the Thirties and Forties with data collection and asks what responsibility tech companies have today to ensure their work does not contribute to evil.

Charlotte Jee then analyses Facebook's stock price slump, asking why it happened and does it really affect the company? The team muses on Facebook as a whole and the fascinating if polarising Zuckerberg.

Finally Macworld's David Price chats about the new MacBook Pros and how Apple has already fixed the major flaw in the high-end model - but why did they ship this way? Is Apple less concerned with quality control these days?

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This week our host Scott Carey is joined by Macworld UK editor Karen Khan to chat about Apple's latest blockbuster results.

Then group production editor Tamlin Magee jumps in to discuss Amazon's working practices following the collective action around Prime Day.

Finally, Scott chats through his experience at the Google Cloud Next conference in San Francisco last week to see how it is trying to compete with the big boys at Amazon and Microsoft.

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This week on the UK Tech Weekly Podcast our host Scott Carey talks to Macworld editor David Price about the ever-controversial Alex Jones and why the big tech companies are finally stepping up their efforts to ban him from their platforms. Editors note: we recorded this on Thursday before Twitter finally started to take some measures against Jones, without outright banning him.

Next our resident phone nerd and consumer tech editor at Tech Advisor Henry Burrell talks about the upcoming Samsung Galaxy Note 9, the latest iPhone X rumours and how Apple and Google are trying to make you use your phone less.

Lastly Techworld editor Charlotte Jee takes us on a trip down memory lane to talk about the utopian vision of the Millennium Experience, how it reflected the values of a New Labour government and its legacy.

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This week our host Scott Carey is joined by Techworld editor Charlotte Jee to discuss the revelation that Google is still tracking users, even if you have that feature disabled, and the wider topic of privacy.

Then games editor at Tech Advisor, Lewis Painter, joins to talk about one of the most hotly anticipated games of the year: Red Dead Redemption 2.

Lastly Macworld UK editor Karen Khan talks about the enduring legacy of the iMac PC 20 years on and how it set Apple on a historic trajectory.

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A quick-fire reaction Apple special, recorded the morning after new iPhones and an Apple Watch were announced at an event in California.

Henry Burrell joins David Price, Ashleigh Macro and Scott Carey to discuss which products we'll be buying, avoiding and coveting over the Christmas period.

Is the new iPhone named terribly? Is it an upgrade at all? What wasn't announced? And does Scott give the new Apple Watch any praise at all? It's all here.

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It's a pop culture episode this week as we do a deep dive into dystopian fiction. Scott Carey is your host as he chats to Dominic Preston and Tamlin Magee about the best novels, films, TV shows and video games set in dystopian universes.

We talk about how the world is closer to fiction than ever before, and how this impacts the way we think about fictional dystopias, and end on a positive note to discuss our favourite utopian fiction too.

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It's episode 105, and David Price takes on hosting duties as the team dissect the best and absolute worst of the week's tech developments.

Scott Carey talks us through the troubling and wide-ranging allegations of sexual misconduct at Google, and discusses how this relates to the tech industry's culture of protected privilege, and to the #metoo movement.

Then Henry Burrell, fresh from a briefing at Apple HQ, reports his distinctly positive first impressions of the iPhone XR, which he would gladly recommend to tech newbie grandmas, and also to Scott.

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David Price is in the host's chair this week, as the team talk about the latest hot tech topics. Tamlin Magee has got the drinks in - futuristic meal-replacement drinks called Soylent, which he forces everyone to try and which are apparently not people.

Then Dominic Preston talks us through the positive and extremely negative sides of Amazon's Black Friday activities, before Sean Bradley attempts to explain why Bitcoin is tanking and what the future holds for crypto currencies. Cheers!

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Two’s a crowd for this week’s games and Christmas pod with Consumer Tech Editor Henry Burrell and Games Editor Lewis Painter. Lewis lines up reviews of the awful Fallout 76 and the excellent online mode of Red Dead Redemption 2 – two polar opposites in how to make a decent online multiplayer game.

We also discuss smartwatches we’ve recently reviewed that left us feeling cold and why Apple is still king of the hill.

And to get into the festive vibe, interspersed throughout as we enter December are our top tech Christmas gift picks, both cheap and indulgent.

Everything we recommend is linked below:

Google Home Hub

Tile Bluetooth tracker

Red Dead Redemption 2 (PS4)

Super Smash Bros – Ultimate (Switch)

Pokémon: Let’s Go, Pikachu! (Switch)

Turtle Beach Elite Pro 2 + Superamp

Amazon Kindle Paperwhite

PlayStation Classic

PlayStation VR Starter Pack

The best budget smartphones

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Happy New Year from the UK Tech Weekly Podcast!

We are back this week to discuss what we have been watching (or not watching) over the festive period, including Scott Carey on the meme-marketed sensation of Bird Box and what this says about Netflix's ability to dominate the cultural conversation. Then Tamlin Magee jumps in to talk about the interactive Black Mirror movie Bandersnatch and why it may have been destined to fail.

Lastly David Price steps out of the hosting chair to talk about bendy iPads and Apple's strange rhetoric.

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This week our host Scott Carey catches up with Sean Bradley and Dominic Preston fresh off the back of the International Consumer Electronics Show (CES) in Las Vegas.

Dom explains why he was surprised, both in a good and bad way, by the latest foldable screen technology and Sean talks about what is going on in the gaming laptop space, as Alienware looks to soften its image.

Then Dom talks about a piece of connected wood and the gang break down the big controversy from the show floor regarding a certain innovative dildo.

We are also announcing the sad news that the UK Tech Weekly Podcast will be going on an indefinite hiatus while we reassess our podcasting output. We would like to thank anyone that has taken the time to listen to us for these one hundred and twelve (112!) episodes and rest assured we will be back in some guise soon.

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This manuscript has been withdrawn by the Author.

Photoreceptors have high energy-demands and a high density of mitochondria that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) of fuel substrates. Although glucose is the major fuel for central nervous system (CNS) brain neurons, in photoreceptors (also CNS), most glucose is not metabolized through OXPHOS but is instead metabolized into lactate by aerobic glycolysis. The major fuel sources for photoreceptor mitochondria remained unclear for almost six decades. Similar to other tissues (like heart and skeletal muscle) with high metabolic rates, photoreceptors were recently found to metabolize fatty acids (palmitate) through OXPHOS. Disruption of lipid entry into photoreceptors leads to extracellular lipid accumulation, suppressed glucose transporter expression, and a duel lipid/glucose fuel shortage. Modulation of lipid metabolism helps restore photoreceptor function. However, further elucidation of the types of lipids used as retinal energy sources, the metabolic interaction with other fuel pathways, as well as the crosstalk among retinal cells to provide energy to photoreceptors is not yet known. In this review, we will focus on the current understanding of photoreceptor energy demand and sources, and potential future investigations of photoreceptor metabolism.

Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM’s catalytic activity in cultured cells, a mechanism which differs from that of functional inhibitors of ASM (FIASMAs). We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASMpromoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.

Excessive lipid deposition is a hallmark of nonalcoholic fatty liver disease (NAFLD). Although much has been learned about the enzymes and metabolites involved in NAFLD, few studies have focused on the role of long non-coding RNAs (lncRNAs) in hepatic lipid accumulation. Here, using in vitro and in vivo models of NAFLD, we found that the lncRNA Gm15622 is highly expressed in the liver of obese mice fed a high-fat diet (HFD) and in murine liver (AML-12) cells treated with free fatty acids. Investigating the molecular mechanism in the liver-enriched expression of Gm15622 and its effects on lipid accumulation in hepatocytes and on NAFLD pathogenesis, we found that Gm15622 acts as a sponge for the microRNA miR-742-3p. This sponging activity increased the expression of the transcriptional regulator sterol regulatory element–binding transcription factor 1c (SREBP-1c) and promoted lipid accumulation in the liver of the HFD mice and AML-12 cells. Moreover, further results indicated that metformin suppresses Gm15622 and alleviates NAFLD-associated lipid deposition in mice. In conclusion, we have identified an lncRNA Gm15622–miR-742-3p–SREBP-1c regulatory circuit associated with NAFLD in mice, a finding that significantly advances our insight into how lipid metabolism and accumulation are altered in this metabolic disorder. Our results also suggest that Gm15622 may be a potential therapeutic target for managing NAFLD.

Nutritional studies rely on various biological specimens for fatty acid (FA) determination, yet it is unclear how levels of serum non-esterified FA (NEFAs) correlate with other circulating lipid pools. Here, we used a high throughput method (< 4 min/sample) based on multisegment injection-non-aqueous-capillary electrophoresis–mass spectrometry (MSI-NACE-MS) to investigate whether specific serum NEFAs have utility as biomarkers of dietary fat intake in women. We first  identified circulating NEFAs correlated with long-term/habitual food intake among pregnant women with contrasting dietary patterns (n=50). Acute changes in serum NEFA trajectories were also studied in non-pregnant women (n=18) following high-dose (5 g/day) fish oil (FO) supplementation or isoenergetic sunflower oil placebo over 56 days. In the cross-sectional study, serum omega-3 (-3) FA correlated with self-reported total -3 daily intake, notably eicosapentaenoic acid (EPA) as its NEFA (r=0.46; p=0.001), whereas pentadecanoic acid was associated with full-fat dairy intake (r=0.43; p=0.002), outcomes consistent with results from  total FA serum hydrolysates. In the intervention cohort, serum -3 NEFAs increased 2.5-fold from baseline within 28 days following FO supplementation, and this increase was most pronounced for EPA (p=0.0004). Unlike for docosahexaenoic acid, circulating EPA as its NEFA also strongly correlated to EPA concentrations measured from erythrocyte phospholipid hydrolysates (r=0.66; p=4.6 x 10-10), and was better suited to detect dietary non-adherence. We conclude that MSI-NACE-MS offers a rapid method to quantify serum NEFAs and objectively monitor dietary fat intake in women that is complementary to diet records or food frequency questionnaires.

Ether lipids (ELs) are lipids characterized by the presence of either an ether linkage (alkyl lipids) or a vinyl ether linkage (i.e. plasmalogens [Pls]) at the sn1 position of the glycerol backbone and they are enriched in PUFAs at the sn2 position. In this review, we highlight that ELs have various biological functions, act as a reservoir for second messengers (such as PUFAs), and have roles in many diseases. Some of the biological effects of ELs may be associated with their ability to regulate ion channels that control excitation-contraction/secretion/mobility coupling and therefore cell physiology. These channels are embedded in lipid membranes, and lipids can regulate their activities directly or indirectly as second messengers or by incorporating into membranes. Interestingly, ELs and EL-derived PUFAs have been reported to play a key role in several pathologies, including neurological disorders, cardiovascular diseases, and cancers. Investigations leading to a better understanding of their mechanisms of action in pathologies have opened a new field in cancer research. In summary, newly identified lipid regulators of ion channels, such as ELs and PUFAs, may represent valuable targets to improve disease diagnosis and advance the development of new therapeutic strategies for managing a range of diseases and conditions.

Ceramides are the predominant lipids in the stratum corneum (SC) and are crucial components for normal skin barrier function. Although the composition of various ceramide classes in the human SC has been reported, that in mice is still unknown, despite mice being widely used as animal models of skin barrier function. Here, we performed LC–MS/MS analyses using recently available ceramide class standards to measure 25 classes of free ceramides and 5 classes of protein-bound ceramides from the human and mouse SC. Phytosphingosine-type ceramides (P-ceramides) and 6-hydroxy sphingosine-type ceramides (H-ceramides), which both contain an additional hydroxyl group, were abundant in human SC (35% and 45% of total ceramides, respectively). In contrast, in mice, P-ceramides and H-ceramides were present at ~1% and undetectable levels, respectively, and sphingosine-type ceramides accounted for ~90%. In humans, ceramides containing α-hydroxy FA were abundant, whereas ceramides containing β-hydroxy FA (B-ceramides) or -hydroxy FA were abundant in mice. The hydroxylated β-carbon in B-ceramides was in the (R)-configuration. Genetic knockout of β-hydroxy acyl-CoA dehydratases in HAP1 cells increased B-ceramide levels, suggesting that β-hydroxy acyl-CoA, an FA-elongation cycle intermediate in the endoplasmic reticulum, is a substrate for B-ceramide synthesis. We anticipate that our methods and findings will help to elucidate the role of each ceramide class in skin barrier formation and in the pathogenesis of skin disorders.

Individuals with Netherton syndrome (NTS) have increased serine protease activity, which strongly impacts the barrier function of the skin epidermis and leads to skin inflammation. Here, we investigated how serine protease activity in NTS correlates with changes in the stratum corneum ceramides, which are crucial components of the skin barrier. We examined two key enzymes involved in epidermal ceramide biosynthesis, glucocerebrosidase (GBA) and acid-sphingomyelinase (ASM). We compared in situ expression levels and activities of GBA and ASM between NTS patients and controls and correlated the expression and activities with i) stratum corneum ceramide profiles, ii) in situ serine protease activity, and iii) clinical presentation of patients. Using activity-based probe labeling, we visualized and localized active, epidermal GBA, and a newly developed in situ zymography method enabled us to visualize and localize active ASM. Reduction in active GBA in NTS patients coincided with increased ASM activity, particularly in areas with increased serine protease activity. NTS patients with scaly erythroderma exhibited more pronounced anomalies in GBA and ASM activities than patients with ichthyosis linearis circumflexa. They also displayed a stronger increase in stratum corneum ceramides processed via ASM. We conclude that changes in the localization of active GBA and ASM correlate with i) altered stratum corneum ceramide composition in NTS patients, ii) local serine protease activity, and iii) the clinical manifestation of NTS. 

Oxidized low-density lipoprotein (oxLDL) is a known risk factor for atherogenesis. This study aimed to reveal structural features of oxLDL present in human circulation related to atherosclerosis. When LDL was fractionated on an anion-exchange column, in vivo-oxLDL, detected by the anti-oxidized phosphatidylcholine (oxPC) monoclonal antibody, was recovered in flow-through and electronegative LDL (LDL(-)) fractions. The amount of the electronegative in vivo-oxLDL, namely oxLDL in LDL(-) fraction, present in patients with acute myocardial infarction (AMI) was three-fold higher than that observed in healthy subjects. Surprisingly, LDL(-) fraction contained apoA1 in addition to apoB, and HDL-sized particles were observed with transmission electron microscopy. In LDL(-) fractions, acrolein adducts were identified at all lysine residues in apoA1, with only a small number of acrolein-modified residues were identified in apoB. The amount of oxPC adducts of apoB was higher in LDL(-) than in L1 fraction as determined using western blotting. The electronegative in vivo-oxLDL was immunologically purified from the LDL(-) fraction with an anti-oxPC monoclonal antibody. Majority of PC species was not oxidized, whereas oxPC and lysoPC did not accumulate. Here, we propose that there are two types of in vivo-oxLDL in human circulating plasma and the electronegative in vivo-oxLDL accompanies oxidized HDL.

Niemann–Pick type C1 (NPC1) disease is a rare genetic condition in which the function of the lysosomal cholesterol transporter NPC1 protein is impaired. Consequently, sphingolipids and cholesterol accumulate in lysosomes of all tissues, triggering a cascade of pathological events that culminate in severe systemic and neurological symptoms. Lysosomal cholesterol accumulation is also a key-factor in the development of atherosclerosis and non-alcoholic steatohepatitis (NASH). In these two metabolic diseases, the administration of plant stanol esters has been shown to ameliorate cellular cholesterol accumulation and inflammation. Given the overlap of pathological mechanisms among atherosclerosis, NASH and NPC1 disease, we sought to investigate whether dietary supplementation with plant stanol esters improves the peripheral features of NPC1 disease. To this end, we used an NPC1 murine model featuring an Npc1 null allele (Npc1^nih), creating a dysfunctional NPC1 protein. Npc1^nih mice were fed a two or six percent plant stanol esters–enriched diet over the course of 5 weeks. During this period, hepatic and blood lipid and inflammatory profiles were assessed. Npc1^nih mice fed the plant stanol–enriched diet exhibited lower hepatic cholesterol accumulation, damage and inflammation than regular chow–fed Npc1^nih mice. Moreover, plant stanol consumption shifted circulating T-cells and monocytes in particular towards an anti-inflammatory profile. Overall, these effects were stronger following dietary supplementation with 6% stanols, suggesting a dose-dependent effect. The findings of our study highlight the potential use of plant stanols as an affordable complementary means to ameliorate disorders in hepatic and blood lipid metabolism and reduce inflammation in NPC1 disease.

Atherogenic LDL particles are physicochemically and metabolically heterogeneous. Can bioactive lipid cargo differentiate LDL subclasses, and thus potential atherogenicity?  What is the effect of statin treatment? Obese, hypertriglyceridemic, hypercholesterolemic males (n=12; Lp(a) <10 mg/dL) received pitavastatin calcium (4mg/day) for 180 days in a single-phase, unblinded study. The lipidomic profiles (23 lipid classes) of five LDL subclasses fractionated from baseline and post-statin plasmas were determined by LC-MS. At baseline and on statin treatment, very small dense LDL (LDL5) was preferentially enriched (up to 3-fold) in specific lysophospholipids (lysophosphatidylcholine (LPC); lysophosphatidylinositol (LPI); lyso-platelet activating factor (LPC(O)); 9,0.2 and 0.14 mol/mol apoB respectively; all p<0.001 versus LDL1-4), suggesting  elevated inflammatory potential per particle. In contrast, lysophosphatidylethanolamine was uniformly distributed among LDL subclasses. Statin treatment markedly reduced absolute plasma concentrations of all LDL subclasses (up to 33.5%), including LPC, LPI and LPC(O) contents (up to -52%), consistent with reduction in cardiovascular risk. Despite such reductions, lipotoxic ceramide load per particle in LDL1-5 (1.5 - 3 mol/mol apoB; 3 - 7 mmol/mol phosphatidylcholine) was either conserved or elevated. Bioactive lipids may constitute biomarkers for the cardiometabolic risk associated with specific LDL subclasses in atherogenic dyslipidemia at baseline, and with residual risk on statin therapy.