Two new regions of Microsoft's Azure cloud will open in Canberra on Tuesday.

Invitation Only Research Event

19 March 2020

Vincent Mignard
Apr 29, 2020; 0:jlr.RA120000628v1-jlr.RA120000628
Research Articles

Deanna L. Davis
Apr 1, 2020; 61:505-522
Research Articles

Timothy D Rohrbach
Apr 27, 2020; 0:jlr.D120000809v1-jlr.D120000809
Methods

Chelsea DeLeon
May 1, 2020; 61:767-777
Research Articles

Eyad Naser
Mar 10, 2020; 0:jlr.RA120000682v1-jlr.RA120000682
Research Articles

In this week's UK Tech Weekly Podcast host Matt Egan is joined by first time podder Tamlin Magee (1:50), online editor at ComputerworldUK.com, to discuss the UK tech implications of this year's Budget, including rural broadband and driverless cars. Then Christina Mercer, assistant online editor at Techworld.com, chats AlphaGo (10:00) and board games following the AI's historic win over world Go champion Lee Sedol. Later, resident Virtual Reality (VR) enthusiast and PCAdvisor.co.uk staff writer Lewis Painter discussed "the big three" VR headset release dates, pricing and features from HTC, Sony Playstation and Oculus Rift (19:00). Finally, UKTW Podcast regular David Price, acting editor at Macworld.co.uk chats about Apple's big upcoming event (28:45).  

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This week host Matt Egan is rejoined by Macworld.co.uk acting editor David Price to chat about Apple's latest Macbook announcements. Then online editor at ComputerworldUK Christina Mercer jumps in to give a break down of Google's fight with the EU over antitrust infringements (13:00). Finally, ex-dating app user Scott Carey, online editor at Techworld.com gives a state of the union on dating apps, from Tinder to Bumble to Happn, if they are good for society and which one is set to corner the market (27:00).  

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Host Matt Egan is joined by producer Chris to talk about the raft of announcements coming out of the Google I/O developer conference this week, including Android N, Google assistant and Allo. Techworld.com editor Charlotte Jee joins in to discuss driverless cars (17:00) following the Queen's speech this week. Finally, acting editor at Macworld.co.uk David Price talks about terrible film adaptations of video games, from Angry Birds to World of Warcraft (29:00). Don't forget to like, share and tell your friends!  

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In Matt Egan's absence first time host Henry Burrell heroically steps in to chat about Pokemon Go with producer Chris. Then fellow staff writer Chris Minasians discusses iOS 10 beta and all of the rumoured features for the latest Apple operating system, including dark mode (10:30). Finally, Lewis Painter, staff writer at PC Advisor, talks about Playstation VR being released for the PS4, pricing and games (23:30).  

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For the second week running hosting duties are taken by Henry Burrell, who is joined by Techworld.com editor Charlotte Jee to discuss the impact of Brexit on the UK's startups. Producer Chris then jumps in to discuss the Pokemon Go launch in the UK and a debate breaks out over whether it is for adults (13:00) Finally, online editor at Computerworld UK Scott Carey brings the latest news around driverless cars, from Tesla's recent struggles and how it may affect the industry in general (25:00)  

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A premature mid-week Google-themed podcast from the team, who reflect on Google's big 4th October event where they launched the Pixel phone and much more. Acting editor of Macworld UK David Price takes the helm and asks Staff Writer at PC Advisor Henry Burrell to wade in and make sense of all the announcements. Expect AI and VR. Then Staff Writer Christopher Minasians (27:45) chats about the new Pokemon Go Plus wearable, and whether a £35 accessory can improve a free mobile game.  

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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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Momentous scenes as the pod celebrates its Golden Jubilee. Matt Egan is joined by some very special guests to congratulate the gang on the milestone while indulging in some points based tech quizzing. Join Chris Martin, Charlotte Jee, Dom Preston and Henry Burrell to recap questions from pods gone by with a new twist, and have a long hard think about what tech will be 50 more episodes from now. The prize? A small bronze jug. Obviously. NB. May not actually be 50 minutes, sorry.  

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The gang muck in to discuss the hottest tech topics of the week (as is tradition). Deputy Editor of Macworld UK David Price asks Jim Martin what was hot at MWC, where phones are birthed or something. Then Techworld Online Editor Thomas MacAuley chats about the government's digital strategy. First question: does it have one? Finally Tamlin Magee, Computerworld UK's Online Editor explains how to hack a robot and why people will almost certainly use this for EVIL. Thanks for listening.  

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After indefinite hiatus the gang is back as David Price asks Henry Burrell all about Google I/O. Is it actually going to be called Android Oreo, and should you download the beta? Second up is Tamlin Magee to get to the bottom of WannaCry and the ransomware troubles of the NHS. What is it, should you be worried and will it happen again? May contain terrible jokes.  

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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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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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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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Scott Carey leads veteran Henry Burrell and first time podder Hannah Williams down the rabbit hole of Google I/O. We discuss which was the most frightening announcement and which was the best - could that actually be the same thing?

We then chat Android P, the beta for Google next OS - cool changes, yes, but how many people will actually ever get it?

Scott and Hannah also weigh in on why Google gets the headlines despite Facebook, Microsoft and Amazon announcements this week.

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Join host Scott Carey as the team dissects Tory meltdown and what it means for tech and the ministers we haven't heard of. What can they actually do to help the country? Charlotte Jee explains.

Then Henry Burrell chats on the new Microsoft Surface Go, an 'affordable' Surface tablet that actually still breaks the bank. Who is it for, and is Microsoft really chasing the iPad market?

David Price rounds up the pod with Musk Corner as everyone's favourite Twitter megalomaniac flies off to Thailand to help with a cave rescue - but should he stay out of it?

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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 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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This week our host Scott Carey catches up on the Google+ breach news and the final demise of the doomed social media network before being joined by consumer technology editor at Tech Advisor, Henry Burrell, to talk about Google's latest batch of smartphones: the Pixel 3 and Pixel 3 XL.

Then Techworld reporter Tamlin Magee joins to talk about the technology-related films screening during the London Film Festival this month and his hopes for more utopian tech-flecked stories in the future.

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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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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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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.

Mass spectrometry (MS) assisted lipidomic tissue analysis is a valuable tool to assess sphingolipid metabolism dysfunction in disease. These analyses can reveal potential pharmacological targets or direct mechanistic studies to better understand the molecular underpinnings and influence of sphingolipid metabolism alterations on disease etiology. But procuring sufficient human tissues for adequately powered studies can be challenging. Therefore, biorepositories, which hold large collections of cryopreserved human tissues, are an ideal retrospective source of specimens. However, this resource has been vastly underutilized by lipid biologists, as the components of optimal cutting temperature compound (OCT) used in cryopreservation are incompatible with MS analyses. Here, we report results indicating that OCT also interferes with protein quantification assays, and that the presence of OCT impacts the quantification of extracted sphingolipids by LC–ESI–MS/MS. We developed and validated a simple and inexpensive method that removes OCT from OCT-embedded tissues. Our results indicate that removal of OCT from cryopreserved tissues does not significantly affect the accuracy of sphingolipid measurements with LC–ESI–MS/MS. We used the validated method to analyze sphingolipid alterations in tumors compared with normal adjacent uninvolved lung tissues from individuals with lung cancer, and to determine the long-term stability of sphingolipids in OCT-cryopreserved normal lung tissues. We show that lung cancer tumors have significantly altered sphingolipid profiles and that sphingolipids are stable for up to 16 years in OCT-cryopreserved normal lung tissues. This validated sphingolipidomic OCT-removal protocol should be a valuable addition to the lipid biologist’s toolbox.

The levels and composition of sphingolipids and related metabolites are altered in aging and common disorders such as diabetes and cancers, as well as in neurodegenerative, cardiovascular, and respiratory diseases. Changes in sphingolipids have been implicated as being an essential step in mitochondria-driven cell death. However, little is known about the precise sphingolipid composition and modulation in mitochondria or related organelles. Here, we used LC–MS/MS to analyze the presence of key components of the ceramide metabolic pathway in vivo and in vitro in purified endoplasmic reticulum (ER), mitochondria-associated membranes (MAM), and mitochondria. Specifically, we analyzed the sphingolipids in the three pathways that generate ceramide: sphinganine in the de novo ceramide pathway, sphingomyelin in the breakdown pathway, and sphingosine in the salvage pathway. We observed sphingolipid profiles in mouse liver, mouse brain, and a human glioma cell line (U251). We analyzed the quantitative and qualitative changes of these sphingolipids during staurosporine (STS)-induced apoptosis in U251 cells. Ceramide, especially C16-ceramide, levels increased during early apoptosis possibly through a conversion from mitochondrial sphinganine and sphingomyelin, but sphingosine and lactosyl- and glucosyl-ceramide levels were unaffected. We also found that ceramide generation is enhanced in mitochondria when sphingomyelin levels are decreased in the MAM. This decrease was associated with an increase in acid sphingomyelinase (ASM) activity in MAM. We conclude that meaningful sphingolipid modifications occur in MAM, the mitochondria, and ER during the early phases of apoptosis.

19 March 2020

1 April 2020

25 April 2020

Accumulation and propagation of hyperphosphorylated tau (p-tau) is a common neuropathological hallmark associated with neurodegeneration of Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and related tauopathies. Extracellular vesicles, specifically exosomes, have recently been demonstrated to participate in mediating tau propagation in brain. Exosomes produced by human induced pluripotent stem cell (iPSC)-derived neurons expressing mutant Tau (mTau), containing the P301L and V337M Tau mutations of FTDP-17, possess the ability to propagate p-tau pathology after injection into mouse brain.  To gain an understanding of the mTau exosome cargo involved in tau pathogenesis, these pathogenic exosomes were analyzed by proteomics and bioinformatics. The data showed that mTau expression dysregulates the exosome proteome to result in (1) proteins uniquely present only in mTau, and not control exosomes, (2) the absence of proteins in mTau exosomes, uniquely present in control exosomes, and (3) shared proteins which were significantly up-regulated or down-regulated in mTau compared to control exosomes. Notably, mTau exosomes (not control exosomes) contain ANP32A (also known as I1PP2A), an endogenous inhibitor of the PP2A phosphatase which regulates the phosphorylation state of p-tau.  Several of the mTau exosome-specific proteins have been shown to participate in AD mechanisms involving lysosomes, inflammation, secretases, and related processes.  Furthermore, the mTau exosomes lacked a substantial portion of proteins present in control exosomes involved in pathways of localization, vesicle transport, and protein binding functions. The shared proteins present in both mTau and control exosomes represented exosome functions of vesicle-mediated transport, exocytosis, and secretion processes. These data illustrate mTau as a dynamic regulator of the biogenesis of exosomes to result in acquisition, deletion, and up- or down-regulation of protein cargo to result in pathogenic mTau exosomes capable of in vivo propagation of p-tau neuropathology in mouse brain. 

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Invitation Only Research Event

GPR120 is implicated as a lipid receptor in the oro-sensory detection of dietary fatty acids. However, the effects of GPR120 activation on dietary fat intake or obesity are not clearly understood. We investigated to determine whether the binding of TUG891, a novel GPR120 agonist, to lingual GPR120 modulates fat preference in mice. We explored the effects of TUG891 on obesity-related hormones and conducted behavioral choice tests on mice to better understand the physiologic relevance of the action of TUG891. In cultured mouse and human taste bud cells (TBCs), TUG891 induced a rapid increase in Ca²⁺ by acting on GPR120. A long-chain dietary fatty acid, linoleic acid (LA), also recruited Ca²⁺ via GPR120 in human and mouse TBCs. Both TUG891 and LA induced ERK1/2 phosphorylation and enhanced in vitro release of glucagon-like peptide-1 from cultured human and mouse TBCs. In situ application of TUG891 onto the tongue of anesthetized mice triggered the secretion of pancreatobiliary juice, probably via the tongue-brain-gut axis. Furthermore, lingual application of TUG891 altered circulating concentrations of cholecystokinin and adipokines, associated with decreased circulating LDL, in conscious mice. In behavioral tests, mice exhibited a spontaneous preference for solutions containing either TUG891 or LA instead of a control. However, addition of TUG891 to a solution containing LA significantly curtailed fatty acid preference. Our study demonstrates that TUG891 binds to lingual GPR120 receptors, activates the tongue-brain-gut axis, and modulates fat preference. These findings may support the development of new fat taste analogs that can change the approach to obesity prevention and treatment.

Plasma lipoprotein (a) [Lp(a)] levels are largely determined by variation in the LPA gene, which codes for apo(a). Genome-wide association studies (GWASs) have identified nonsynonymous variants in LPA that associate with low Lp(a) levels, although their effect on apo(a) function is unknown. We investigated two such variants, R990Q and R1771C, which were present in four null Lp(a) individuals, for structural and functional effects. Sequence alignments showed the R990 and R1771 residues to be highly conserved and homologous to each other and to residues associated with plasminogen deficiency. Structural modeling showed both residues to make several polar contacts with neighboring residues that would be ablated on substitution. Recombinant expression of the WT and R1771C apo(a) in liver and kidney cells showed an abundance of an immature form for both apo(a) proteins. A mature form of apo(a) was only seen with the WT protein. Imaging of the recombinant apo(a) proteins in conjunction with markers of the secretory pathway indicated a poor transit of R1771C into the Golgi. Furthermore, the R1771C mutant displayed a glycosylation pattern consistent with ER, but not Golgi, glycosylation. We conclude that R1771 and the equivalent R990 residue facilitate correct folding of the apo(a) kringle structure and mutations at these positions prevent the proper folding required for full maturation and secretion. To our knowledge, this is the first example of nonsynonymous variants in LPA being causative of a null Lp(a) phenotype.

Myelin is a unique lipid-rich membrane structure that accelerates neurotransmission and supports neuronal function. Sphingolipids are critical myelin components. Yet sphingolipid content and synthesis have not been well characterized in oligodendrocytes, the myelin-producing cells of the CNS. Here, using quantitative real-time PCR, LC-MS/MS-based lipid analysis, and biochemical assays, we examined sphingolipid synthesis during the peak period of myelination in the postnatal rat brain. Importantly, we characterized sphingolipid production in isolated oligodendrocytes. We analyzed sphingolipid distribution and levels of critical enzymes and regulators in the sphingolipid biosynthetic pathway, with focus on the serine palmitoyltransferase (SPT) complex, the rate-limiting step in this pathway. During myelination, levels of the major SPT subunits increased and oligodendrocyte maturation was accompanied by extensive alterations in the composition of the SPT complex. These included changes in the relative levels of two alternative catalytic subunits, SPTLC2 and -3, in the relative levels of isoforms of the small subunits, ssSPTa and -b, and in the isoform distribution of the SPT regulators, the ORMDLs. Myelination progression was accompanied by distinct changes in both the nature of the sphingoid backbone and the N-acyl chains incorporated into sphingolipids. We conclude that the distribution of these changes among sphingolipid family members is indicative of a selective channeling of the ceramide backbone toward specific downstream metabolic pathways during myelination. Our findings provide insights into myelin production in oligodendrocytes and suggest how dysregulation of the biosynthesis of this highly specialized membrane could contribute to demyelinating diseases.

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (^–/–) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.­

Trying to read a Google BigQuery table that contains a variable that is defined as an array of records might result in an error and cause SAS to shut down. This issue occurs when one of the variables contained in

When you issue a LIBNAME statement for a Google BigQuery database without including the SCHEMA= option, all tables in the project are shown when the libref is expanded. However, if you try to acces

When you bulk load data into a Google BigQuery database, you might encounter this error: "Error while reading data, error message: CSV table encountered too many errors, giving up...Error detected while parsing row starting at position: 0...Data