Games! Tech Advisor's Lewis Painter and Dom Preston school Henry Burrell and Techword's Scott Carey on the haps from E3. What does E3 stand for? What is a rabbid? Which games have eagles in them? All the issues. Scott then talks us through Uber's latest mishaps, which by now are not funny - will the company survive the mess its CEO has led it into?  

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We're back this week to bring you all the hot news from E3 and some cooler takes on everything Apple announced at its WWDC developer conference a few weeks back.

To help us do that Macworld UK editor Karen Khan runs through all the iOS and macOS Mojave updates Apple users can look forward to later this year.

Then Tech Advisor staff writer Sean Bradley is on hand for a whistlestop tour of all of the big gaming announcements from E3 in LA so far, including Gears of War, Death Stranding and The Last Of Us 2.

See you next week!

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Linear eMerge E3 versions 1.00-06 and below arbitrary file upload remote root code execution exploit.

ABSTRACT

The multifunctional nature of viral proteins is essentially driven by posttranslational modifications (PTMs) and is key for the successful outcome of infection. For influenza A viruses (IAVs), a composite pattern of PTMs regulates the activity of viral proteins. However, almost none are known that target the PB2 replication protein, except for inducing its degradation. We show here that PB2 undergoes a nonproteolytic ubiquitination during infection. We identified E3 ubiquitin ligases catalyzing this ubiquitination as two multicomponent RING-E3 ligases based on cullin 4 (CRL4s), which are both contributing to the levels of ubiquitinated forms of PB2 in infected cells. The CRL4 E3 ligase activity is required for the normal progression of the viral cycle and for maximal virion production, indicating that the CRL4s mediate a ubiquitin signaling that promotes infection. The CRL4s are recruiting PB2 through an unconventional bimodal interaction with both the DDB1 adaptor and DCAF substrate receptors. While able to bind to PB2 when engaged in the viral polymerase complex, the CRL4 factors do not alter transcription and replication of the viral segments during infection. CRL4 ligases catalyze different patterns of lysine ubiquitination on PB2. Recombinant viruses mutated in the targeted lysines showed attenuated viral production, suggesting that CRL4-mediated ubiquitination of PB2 contributes to IAV infection. We identified K29-linked ubiquitin chains as main components of the nonproteolytic PB2 ubiquitination mediated by the CRL4s, providing the first example of the role of this atypical ubiquitin linkage in the regulation of a viral infection.

IMPORTANCE Successful infection by influenza A virus, a pathogen of major public health importance, involves fine regulation of the multiple functions of the viral proteins, which often relies on post-translational modifications (PTMs). The PB2 protein of influenza A viruses is essential for viral replication and a key determinant of host range. While PTMs of PB2 inducing its degradation have been identified, here we show that PB2 undergoes a regulating PTM signaling detected during infection, based on an atypical K29-linked ubiquitination and mediated by two multicomponent E3 ubiquitin ligases. Recombinant viruses impaired for CRL4-mediated ubiquitination are attenuated, indicating that ubiquitination of PB2 is necessary for an optimal influenza A virus infection. The CRL4 E3 ligases are required for normal viral cycle progression and for maximal virion production. Consequently, they represent potential candidate host factors for antiviral targets.

RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell–like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 (Smad3+/−), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients.Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.

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The Electronic Entertainment Expo, the signature video game industry event held each June, has been cancelled because of fears of the coronavirus.

The Entertainment Software Association may have cancelled E3 2020 due to COVID-19, but it's still committed to holding an event next year. The organization has announced that E3 will return between June 15th and June 17th, 2021. It characterized the future expo as a "reimagined" event, although that's the language it used for its since-scrapped 2020 gathering. It won't be surprising if the 2021 event is really a look at what you might have seen this year, just with a different mix of games.

Canceled Wednesday, this year's E3 was particularly anticipated because new consoles from Sony and Microsoft are due to be released by the end of the year.

Summer Game Fest, spearheaded by Game Awards architect Geoff Keighley, already has Microsoft, Sony, Electronic Arts, Bethesda and Activision on board.

Cancellation of LA games convention over coronavirus fears leaves Microsoft hastily redrawing plans to promote new console

Microsoft will unveil its Xbox Series X console via an online event in June after it has been confirmed that the major games conference E3 has been cancelled.

The launch was set to be a major feature of the annual Los Angeles convention, which attracts 65,000 visitors a year and broadcasts press events to millions worldwide. On Wednesday, event organiser the Electronic Entertainment Association announced on its website that E3 2020 would not take place due to concerns over the coronavirus.

E3 has always been an important moment for Team Xbox. Given this decision, this year we'll celebrate the next generation of gaming with the @Xbox community and all who love to play via an Xbox digital event. Details on timing and more in the coming weeks https://t.co/xckMKBPf9h

Quotation - dated 20.10.2011 - Disposal of Office Staff Car bearing No. WE3 02E 5189 - Display of Sale Notice, Terms and Conditions on Ministrys website - reg.

The new trailer for the long-awaited video game Beyond Good and Evil 2 was just revealed at E3 2018. Here's all you need to know about its trailer, release date, platforms, plot and more.