Shwetha K. Shetty
Apr 1, 2020; 61:546-559
Methods

Delphine Fontaine
Apr 7, 2020; 0:jlr.RA120000634v1-jlr.RA120000634
Research Articles

Inês Magro dos Reis
Apr 14, 2020; 0:jlr.RA120000632v1-jlr.RA120000632
Research Articles

Jeroen van Smeden
Apr 7, 2020; 0:jlr.RA120000639v1-jlr.RA120000639
Research Articles

Ilya Levental
May 1, 2020; 61:592-594
Commentary

Stephen G. Young
May 1, 2020; 61:589-590
Editorials

Zinc is a critical element for insulin storage in the secretory granules of pancreatic beta cells. The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions. A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide change contributes to increased susceptibility to type-2 diabetes (T2D), but it remains unclear how the high risk variant (Arg-325), which is also a higher frequency (>50%) allele, is correlated with zinc transport activity. Here, we compared the activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325). The Arg-325 variant was found to be more active than the Trp-325 form following induced expression in HEK293 cells. We further examined the functional consequences of changing lipid conditions to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis. Purified ZnT8 variants in proteoliposomes exhibited more than 4-fold functional tunability by the anionic phospholipids, lysophosphatidylcholine and cholesterol. Over a broad range of permissive lipid compositions, the Arg-325 variant consistently exhibited accelerated zinc transport kinetics versus the Trp-form. In agreement with the human genetic finding that rare loss-of-function mutations in ZnT8 are associated with reduced T2D risk, our results suggested that the common high risk Arg-325 variant is hyperactive, and thus may be targeted for inhibition to reduce T2D risk in the general populations.

This week host Matt Egan is joined by Ashleigh Allsopp, engagement editor of Macworld UK and physical bookshelf enthusiast to discuss eBooks and eReaders following the big Nook and Amazon Kindle news in the week (1:40). Producer Chris Martin chips in to talk about the death of the father of email, Ray Tomlinson, this week and the growth of workplace tools like Slack that are trying to reduce the amount we use email (12:30). Finally regular contributor and acting editor at Macworld UK David Price talks about Apple ransomware (24:00).  

See acast.com/privacy for privacy and opt-out information.

This week host Matt Egan is joined by regular podder David Price, acting editor of Macworld.co.uk, to discuss Apple's not so awesome results and stalling iPhone sales. Then online editor Scott Carey jumps in to discuss Facebook's far better results and how it has come to dominate the mobile advertising market (15:00) Finally, producer Chris comes out from behind the glass to discuss Nintendo's secretive NX console and having to wait for the new Zelda game (28:00).  

See acast.com/privacy for privacy and opt-out information.

In this week's fiery episode host Matt Egan talks war and gaming with Macworld UK's David Price, the greatest graphics ever with Christopher Minasians of PC Advisor and Macworld UK (14:21), and the best networks in the UK with fellow PCA and MWUK stalwart Henry Burrell (25:23). Expect songs and laughter, and tech ever after.  

See acast.com/privacy for privacy and opt-out information.

This week host Matt Egan is joined by producer Chris to talk about the recent batch of new Pebble devices and the smartwatch market. Staff writer at PC Advisor Lewis Painter joins in to talk about the death of the hoverboard (13:00). Finally, regular podder David Price comes on to talk about Appl...oh Twitter, specifically changes to the character limit and the sad loss of the @ (24:00).  

See acast.com/privacy for privacy and opt-out information.

This week host Matt Egan is joined by first time podder and editor of PC Advisor Jim Martin to chat Microsoft Windows 10 anniversary updates and the impact on Microsoft Surface devices. Producer Chris then comes on to chat about Sky's two big NOW TV announcements, and the future of television and broadband (16:00). Finally, UKTW podcast regular David Price chats about the impact technology is having on our holidays (26:30).  

See acast.com/privacy for privacy and opt-out information.

Hosting duties fall to Henry Burrell this week as he discusses the deadline for the free Microsoft Windows 10 update with Chris Minasians, staff writer at PC Advisor. Scott Carey, online editor at Techworld.com jumps in to talk about why the Verizon deal for Yahoo is ridiculous and charts the missteps that got the company to this point (15:00). Finally, regular guest David Price discusses Apple's less than stellar financial results and if the iPhone is plateauing (26:00).  

See acast.com/privacy for privacy and opt-out information.

This week Ashleigh Allsopp is simultaneously fascinated and worried by the UK launch of Amazon's Dash buttons, and discusses the many wonderful and not-so-wonderful things they enable you to buy on a drunken whim. Then David Price takes his turn to shine a spotlight on Apple's mysterious tax affairs (12:20) and tries to explain why the Irish government doesn't want to be given 13 billion euros. Finally a surprisingly riled-up Neil Bennett explains why women wearing headphones are not fair game for dimwitted pick-up artists (25:00), and ponders the social conventions surrounding the place of technology in each of our lives.  

See acast.com/privacy for privacy and opt-out information.

Matt Egan is back on hosting duties this week to break down the demise of the Samsung Galaxy Note 7 with producer Chris. Then staff writer at PC Advisor Lewis Painter comes on to talk about the Playstation VR release, games and pricing and compares it to the flagging Oculus Rift and HTC Vive (13:00). Finally, Scott Carey, online editor at Computerworld UK reports back from the biggest tech conference in the world, Dreamforce, chats about Salesforce's rumoured bid for Twitter and tries to make CRM interesting (25:00).  

See acast.com/privacy for privacy and opt-out information.

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.  

See acast.com/privacy for privacy and opt-out information.

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).  

See acast.com/privacy for privacy and opt-out information.

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.  

See acast.com/privacy for privacy and opt-out information.

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.  

See acast.com/privacy for privacy and opt-out information.

Techworld Editor Charlotte Jee conducts the tech orchestra this week, trying to get a tune out of this cold, creaking week. Online Editor at Computerworld UK Scott Carey lets us know all about Snapchat's upcoming IPO, billions of dollars, and the gang comes to the realisation they'll perhaps never understand what it's for. Then Senior Staff Writer at PC Advisor Henry Burrell recaps on Google and LG's launch of Android Wear 2.0 and ask - frankly - is it a big deal? Finally Acting Editor at Macworld UK David Price discusses Apple's rumoured plans to move manufacturing to India, which inevitably moves us on to Tech Trumps.  

See acast.com/privacy for privacy and opt-out information.

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?  

See acast.com/privacy for privacy and opt-out information.

The big story of the week is Wikileaks' CIA data dump, and we sandwich that topic between Apple's upcoming event and Nintendo Switch hardware issues. Lewis Painter kicks things off with Apple's (fingers crossed) late March event where we hope to see iPads, iMacs and get our six monthly fix of Jony Ive product videos. Then (13 minutes) Tamlin Magee tackles Vault 7 and the CIA's apparent ability to take control of iPhones and TVs, bypassing encryption. Will continuous leaks change anything? Finally (26 minutes) Dom Preston talks about his time over the last few weeks playing Zelda on the Nintendo Switch and why we should be a bit concerned about dodgy controllers.  

See acast.com/privacy for privacy and opt-out information.

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?  

See acast.com/privacy for privacy and opt-out information.

Back with a bumper edition after the Easter break, as Henry Burrell takes Scott Carey, David Price and Dom Preston on a chat odyssey to discuss Facebook's F8 conference. Will chat bots ever be good and who uses QR codes? The gang then discusses Apple's out of character decision to brief journos on the Mac Pro and even admit they got it wrong. Finally we talk about Nintendo stopping production of the NES Classic and whether there's more affordable retro goodness around the corner.  

See acast.com/privacy for privacy and opt-out information.

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.  

See acast.com/privacy for privacy and opt-out information.

It's a bumper pod! David Price leads Ashleigh Macro and Henry Burrell down the topical rabbit hole to discuss why Black Friday largely sucks, but is an interesting venture for publishers as well as consumers. Who else bought a Switch?

We then tackle the Mac root issue that hit headlines worldwide before tearing the Pixel Buds a new one. And we all downloaded Animal Crossing: Pocket Camp to see what the fuss is about.

See acast.com/privacy for privacy and opt-out information.

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.

See acast.com/privacy for privacy and opt-out information.

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.

See acast.com/privacy for privacy and opt-out information.

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.

See acast.com/privacy for privacy and opt-out information.

A double Google header as Henry Burrell leads Scott Carey and Sean Bradley down the tech rabbit hole. Alphabet's most famous outlet has redesigned Gmail for desktop, but what does that mean for businesses and consumers. Will anyone notice?

Then what is Chat? Not Google Chat or Android Chat, mind - just Chat. Will the Google-led initiative really transform text messaging on Android or is it doomed to forever to be a fragmented mess?

Sean then talks us through the latest AMD processors to challenge Intel. Intel hasn't had the best of year's after Apple announced it is going solo. Is there a change afoot?

See acast.com/privacy for privacy and opt-out information.

Oh boy what a meaty session we have for you as Christina Mercer, Somrata Sarkar, David Price and Henry Burrell tackle three whopics (whopping topics) head on.

Somrata takes us into the sometimes scary thoughts of our own digital afterlives. Should we be worried that we'll end up as misrepresentative chat bots one day? Who will have the authority to police the companies that harvest our data?

Then Christina explains the knife edge America is on when it comes to net neutrality. Despite recent hope, there's still a chance the web across the pond will be ruthlessly metered and segmented.

Finally David asks us if we've checked our unused email accounts recently, as there might be a lot of desperate noodle companies in there begging you to stay on their mailing lists.

See acast.com/privacy for privacy and opt-out information.

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.

See acast.com/privacy for privacy and opt-out information.

This week we are talking about Apple's New York event, where Digital Arts editor Neil Bennett was in attendance for the launch of a fresh new iPad, Mac Mini and a new Macbook Air. We discuss if the Apple laptop range is a mess and who the new iPad is really for.

Later on we have games editor at Tech Advisor Lewis Painter on to talk about the biggest game of the year: Red Dead Redemption 2 and if it lives up to the hype, and if it's worth the 'crunch' put in by overworked Rockstar developers.

See acast.com/privacy for privacy and opt-out information.

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!

See acast.com/privacy for privacy and opt-out information.

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

See acast.com/privacy for privacy and opt-out information.

This manuscript has been withdrawn by the Author.

Gram-negative bacteria possess an asymmetric outer membrane (OM) composed primarily of lipopolysaccharides (LPS) on the outer leaflet and phospholipids (PLs) on the inner leaflet. Loss of this asymmetry due to mutations in the lipopolysaccharide (LPS) biosynthesis or transport pathways causes externalization of PLs to the outer leaflet of the OM and leads to OM permeability defects. Here, we employed metabolic labeling to detect a compromised OM in intact bacteria. Phosphatidylcholine synthase (Pcs) expression in Escherichia coli allowed for incorporation of exogenous propargylcholine (PCho) into phosphatidyl(propargyl)choline (PPC) and for incorporation of exogenous 1-azidoethyl-choline (AECho) into phosphatidyl(azidoethyl)choline (AEPC) as confirmed by LC-MS analyses. A fluorescent copper-free click reagent poorly labeled AEPC in intact wild-type cells, but readily labeled AEPC from lysed cells. Fluorescence microscopy and flow cytometry analyses confirmed the absence of significant AEPC labeling from intact wild-type E. coli strains, and revealed significant AEPC labeling in an E. coli LPS transport mutant (lptD4213) and an LPS biosynthesis mutant (E. coli lpxC101). Our results suggest that metabolic PL labeling with AECho is a promising tool to detect a compromised bacterial OM, reveal aberrant PL externalization, and identify or characterize novel cell-active inhibitors of LPS biosynthesis or transport.

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.

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.