Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behcet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position ). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ~40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.

Mass spectrometry (MS)-based proteomics has great potential for overcoming the limitations of antibody-based immunoassays for antibody-independent, comprehensive, and quantitative proteomic analysis of single cells. Indeed, recent advances in nanoscale sample preparation have enabled effective processing of single cells. In particular, the concept of using boosting/carrier channels in isobaric labeling to increase the sensitivity in MS detection has also been increasingly used for quantitative proteomic analysis of small-sized samples including single cells. However, the full potential of such boosting/carrier approaches has not been significantly explored, nor has the resulting quantitation quality been carefully evaluated. Herein, we have further evaluated and optimized our recent boosting to amplify signal with isobaric labeling (BASIL) approach, originally developed for quantifying phosphorylation in small number of cells, for highly effective analysis of proteins in single cells. This improved BASIL (iBASIL) approach enables reliable quantitative single-cell proteomics analysis with greater proteome coverage by carefully controlling the boosting-to-sample ratio (e.g. in general <100x) and optimizing MS automatic gain control (AGC) and ion injection time settings in MS/MS analysis (e.g. 5E5 and 300 ms, respectively, which is significantly higher than that used in typical bulk analysis). By coupling with a nanodroplet-based single cell preparation (nanoPOTS) platform, iBASIL enabled identification of ~2500 proteins and precise quantification of ~1500 proteins in the analysis of 104 FACS-isolated single cells, with the resulting protein profiles robustly clustering the cells from three different acute myeloid leukemia cell lines. This study highlights the importance of carefully evaluating and optimizing the boosting ratios and MS data acquisition conditions for achieving robust, comprehensive proteomic analysis of single cells.

HNF4α is a nuclear receptor produced as 12 isoforms from two promoters by alternative splicing. To characterize the transcriptional capacities of all 12 HNF4α isoforms, stable lines expressing each isoform were generated. The entire transcriptome associated with each isoform was analyzed as well as their respective interacting proteome. Major differences were noted in the transcriptional function of these isoforms. The α1 and α2 isoforms were the strongest regulators of gene expression whereas the α3 isoform exhibited significantly reduced activity. The α4, α5, and α6 isoforms, which use an alternative first exon, were characterized for the first time, and showed a greatly reduced transcriptional potential with an inability to recognize the consensus response element of HNF4α. Several transcription factors and coregulators were identified as potential specific partners for certain HNF4α isoforms. An analysis integrating the vast amount of omics data enabled the identification of transcriptional regulatory mechanisms specific to certain HNF4α isoforms, hence demonstrating the importance of considering all isoforms given their seemingly diverse functions.

The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.

Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels.

Signaling networks process intra- and extracellular information to modulate the functions of a cell. Deregulation of signaling networks results in abnormal cellular physiological states and often drives diseases. Network responses to a stimulus or a drug treatment can be highly heterogeneous across cells in a tissue because of many sources of cellular genetic and non-genetic variance. Signaling network heterogeneity is the key to many biological processes, such as cell differentiation and drug resistance. Only recently, the emergence of multiplexed single-cell measurement technologies has made it possible to evaluate this heterogeneity. In this review, we categorize currently established single-cell signaling network profiling approaches by their methodology, coverage, and application, and we discuss the advantages and limitations of each type of technology. We also describe the available computational tools for network characterization using single-cell data and discuss potential confounding factors that need to be considered in single-cell signaling network analyses.

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.

Marriage vows are one thing, but the public service Code of Conduct, that's serious.

It's another front in the long-running rivalry beneath north and south in the nation's capital.

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

Invitation Only Research Event

Event participants

Professor Robert Shiller, Sterling Professor of Economics, Yale University
Chair: Marianne Schneider-Petsinger, Research Fellow, US and the Americas Programme Chatham House

4 March 2020 , Volume 96, Number 2

2 April 2020

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

Gernot F. Grabner
Apr 29, 2020; 0:jlr.RA119000516v1-jlr.RA119000516
Research Articles

Dong-Jae Jun
May 1, 2020; 61:746-757
Research Articles

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

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

Henry J. Pownall
May 1, 2020; 61:595-597
Commentary

In the inaugural episode of the UK Tech Weekly Podcast host Matt Egan discusses Apple's disastrous Error 53 with David Price, acting editor of Macworld UK. Techworld.com editor Charlotte Jee discusses the London mayoral candidates views on the UK tech industry, including Zach Goldsmith's anti-Uber statement, and online editor Scott Carey jumps in with some inane ideas around fibre broadband. Finally the team talk about YouTube licensing rights, despite knowing absolutely nothing about the subject.  

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In the second episode of the UK Tech Weekly Podcast host Matt Egan discusses the Mobile World Congress (MWC) with producer Chris Martin before he jets off to Barcelona, including what device launches we are expecting from the likes of LG, Sony and Samsung. Acting editor at Macworld.co.uk David Price chats about the row between Apple and the FBI over encryption (14:50). Finally Scott Carey from Techworld.com discusses challenger banks (25:00) what they are, what the technology looks like and why you should care.  

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In this week's UK Tech Weekly Podcast host Matt Egan is joined by PC Advisor staff writer Chris Minasians chats about Facebook's new like buttons, the team has contracted smartphone fever from the Mobile World Conference in Barcelona and finally, acting editor of Macworld UK David Price, discusses Donald Trump boycotting Apple.  

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In this week's UK Tech Weekly Podcast host Matt Egan discusses VR with Lewis Painter, staff writer at PC Advisor and Chris Martin, consumer tech editor at PC advisor. Then Chris Minasians, staff writer at Macworld UK vents about how technology is destroying social interactions IRL (11:30), light stuff for your weekend listening pleasure! Finally (23:00) acting editor of Macworld UK David Price and the gang chat about paid-for-streaming advocate Kanye West doing a naughty and pirating music software.  

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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).  

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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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In this week's UK Tech Weekly Podcast host Matt Egan is joined by acting editor at Macworld.co.uk David Price to discuss this week's Apple event announcements, from the iPhone SE to the iPad Pro and iOS 9.3. Then first time podder and staff writer at Macworld.co.uk Henry Burrell wades in to discuss Facebook dropping its support for Blackberry and the future of the under-fire mobile phone maker (19:45). Finally, online editor at Techworld.com Scott Carey chats coding in schools following the BBC micro:bit news and how it differs from the Raspberry Pi (27:40).  

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In this week's UK Tech Weekly Podcast host Matt Egan is joined by online editor at Techworld.com Scott Carey to discuss all of the news coming out of Microsoft's Build 2016 developer conference, before being joined by producer Chris to talk about the company's genocidal AI chatbot Tay's public meltdown (13:00). Then, acting editor at Macworld.co.uk David Price jumps in to discuss the apparent resolution to the Apple vs FBI fight (29:00).  

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This week host Matt Egan kicks things off by chatting to staff writer Lewis Painter about the (genuinely) impressive Huawei P9 phone release. Then, acting editor at Macworld.co.uk David Price jumps in to discuss Whatsapp encryption (12:30) and the Panama Papers. Finally, Christina Mercer, online editor at Techworld.com, introduces you to the wonderful world of Li-Fi (24:30).  

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Producer Chris dives in this week to discuss the HTC 10 release, and why it's difficult to get excited about good mobile phones. Then Techworld.com editor Charlotte Jee chats Facebook chatbots and other F8 news (12:30). Finally, editor at Digitalartsonline.co.uk Neil Bennett jumps in to discuss the new Amazon e-reader (31:00) Kindle Oasis and why everyone is kicking off about the price.  

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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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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).  

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On this week's UK Tech Weekly podcast host Matt Egan is joined by Macworld UK and PC Advisor Staff Writer Lewis Painter, who has spent the past week in virtual reality, and is beyond excited to tell us all about the amazing HTC Vive. Then regular podder David Price, acting editor of Macworld UK, brings us tales from the murky world of Bitcoin, and explains how the crypto-currency is bringing about new tech that may revolutionise the finance industry (16:30) Finally, producer Chris throws aside his mic stand to discuss Sky Q and the current options in media streaming and TV. (25:30).  

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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.  

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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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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).  

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This week host Matt Egan is joined by PC Advisor staff writer Chris Minasians to chat about the AMD Radeon RX 480 graphics card and what this could mean for the future of virtual reality games. Fellow staff writer at PC Advisor Henry Burrell jumps in to talk about the "not terrible" Windows 10 phone as he starts using the Microsoft Lumia 950 and can't see what everyone's beef with it is (13:00). Finally Ashleigh Allsopp, engagement editor at Macworld UK chats about using your technology at concerts (24:30).  

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Host Matt Egan is joined this week by Henry Burrell, staff writer at Macworld UK to talk about the EU referendum website crashing Lewis Painter, staff writer at PC Advisor, jumps in to chat about Oculus Rift games and how immersive they are. Finally regular David Price comes on to talk about Apple's upcoming WWDC software developer conference and what we can (and cannot) expect.  

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Host Matt Egan is joined by Online Editor at Techworld.com Scott Carey to break down Microsoft's mega acquisition of LinkedIn. Staff Writer at PC Advisor Chris joins in to discuss all of the news coming out of E3 and how Xbox and Playstation are set to battle it out again this summer, or will Nintendo and Zelda steal the show? (13:00). Finally, David Price comes on to talk about all of the news coming out of Apple's WWDC developer conference this week, from Hair Force One to watchOS, tvOS, macOS and iOS (26:30) And please do share, rate and review the UK Tech Weekly Podcast.  

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Editor Matt Egan sits down with staff writer at PC Advisor Lewis Painter to chat about Samsung's S8 rumours. Editor of Techworld.com Charlotte Jee discusses all the goings on from London Tech Week and if London is as much of a tech city as it says it is (12:00). Finally, regular guest David Price, editor at Macworld UK, comes on to discuss Mark Zuckerberg's webcam paranoia and cyber security (22:00).  

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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).  

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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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Macworld UK’s Acting Editor David Price takes the reins for this edition, and is joined by Online Editor of Computerworld UK Scott Carey to chat about billions and billions of pounds and the acquisition of ARM by SoftBank. Second up, Staff Writer at PC Advisor and Macworld UK Christopher Minasians plugs in to the haunting world of graphics cards and makes sense of it all for the rest of us. Digital Arts Staff Writer Mimi Launder then explains why Twitter has slapped a troll right in the face in order to stand up to Internet bullying.  

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