BACKGROUND Preclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor.METHODS In this phase I trial, patients received either 1.5 × 106 MICs per kg BW on day –2 (n = 3, group A), or 1.5 × 108 MICs per kg BW on day –2 (n = 3, group B) or day –7 (n = 4, group C) before living donor kidney transplantation in addition to post-transplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360.RESULTS MIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 1010 donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19+CD24hiCD38hi transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19- and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature.CONCLUSION MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.TRIAL REGISTRATION EudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220FUNDING Federal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.

Colitis caused by Clostridium difficile infection is a growing cause of human morbidity and mortality, especially after antibiotic use in health care settings. The natural immunity of newborn infants and protective host immune mediators against C. difficile infection are not fully understood, with data suggesting that inflammation can be either protective or pathogenic. Here, we show an essential role for IL-17A produced by γδ T cells in host defense against C. difficile infection. Fecal extracts from children with C. difficile infection showed increased IL-17A and T cell receptor γ chain expression, and IL-17 production by intestinal γδ T cells was efficiently induced after infection in mice. C. difficile–induced tissue inflammation and mortality were markedly increased in mice deficient in IL-17A or γδ T cells. Neonatal mice, with naturally expanded RORγt+ γδ T cells poised for IL-17 production were resistant to C. difficile infection, whereas elimination of γδ T cells or IL-17A each efficiently overturned neonatal resistance against infection. These results reveal an expanded role for IL-17–producing γδ T cells in neonatal host defense against infection and provide a mechanistic explanation for the clinically observed resistance of infants to C. difficile colitis.

Infection with the Gram-negative bacterium Helicobacter pylori remains the most important modifiable risk factor for the development of gastric cancer, a leading cause of cancer-related deaths worldwide. How the interactions between H. pylori and its host shape the gastric environment during chronic infection warrants further investigation. In this issue of the JCI, Palrasu et al. used human cell lines and mouse models to provide mechanistic insight into H. pylori’s ability to delay apoptosis in gastric epithelial cells by actively driving the degradation of a proapoptotic factor, SIVA1. Their findings suggest that promoting the survival of gastric epithelial cells has implications not only for H. pylori pathogenesis but for host tumorigenesis.

Approximately half of the world’s population is infected with the stomach pathogen Helicobacter pylori. Infection with H. pylori is the main risk factor for distal gastric cancer. Bacterial virulence factors, such as the oncoprotein CagA, augment cancer risk. Yet despite high infection rates, only a fraction of H. pylori–infected individuals develop gastric cancer. This raises the question of defining the specific host and bacterial factors responsible for gastric tumorigenesis. To investigate the tumorigenic determinants, we analyzed gastric tissues from human subjects and animals infected with H. pylori bacteria harboring different CagA status. For laboratory studies, well-defined H. pylori strain B128 and its cancerogenic derivative strain 7.13, as well as various bacterial isogenic mutants were employed. We found that H. pylori compromises key tumor suppressor mechanisms: the host stress and apoptotic responses. Our studies showed that CagA induces phosphorylation of XIAP E3 ubiquitin ligase, which enhances ubiquitination and proteasomal degradation of the host proapoptotic factor Siva1. This process is mediated by the PI3K/Akt pathway. Inhibition of Siva1 by H. pylori increases survival of human cells with damaged DNA. It occurs in a strain-specific manner and is associated with the ability to induce gastric tumor.

Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmaco-resistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local Iba1+ microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting MapT suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor–driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms.

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR–expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.

Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.

I’ve got a new re-release! The title and cover for Road to the Sun were a little too dreamy and not really indicative of the actiony-suspensey vibe of the plot. Dar Albert designed an awesome new cover, and the brilliant Annabeth Albert (no relation!) suggested the new title. You can borrow in KU for the next three months […]

Microsoft plans to add trackpad and mouse support to its Word, Excel, and PowerPoint apps for iPad by the fall, according to TechCrunch and The Verge.

iPadOS 13.4 introduced trackpad and mouse support on all iPad models released in the past four to five years. Keyboards with trackpads include Apple's Magic Keyboard and Brydge's Pro+ for the iPad Pro and Logitech's Combo for the 10.2-inch iPad and the 10.5-inch iPad Air.

When using a trackpad, the cursor displays as a circle on the screen, popping up only when you have a finger on the trackpad. The circle then morphs into various other shapes when hovering over app icons, text fields, or other on-screen elements.

This article, "Microsoft to Add Trackpad Support to Word, Excel, and PowerPoint Apps on iPad" first appeared on MacRumors.com

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Amazon is taking up to $100 off the Apple Watch Series 5 this week, with prices starting at $299.99 for the 40mm GPS models. Only the Gold Aluminum Case with Pink Sport Band is available at this price. If you order today, the Apple Watch should arrive sometime next week.

Note: MacRumors is an affiliate partner with Amazon. When you click a link and make a purchase, we may receive a small payment, which helps us keep the site running.

The Apple Watch Series 5 was released in September 2019 with a new OLED screen that supports an always-on feature, which represents the biggest change to the Series 5 models. The newest Apple Watch is available in 40mm and 44mm sizes, and it has the overall same design as the Series 4 models.

$100 OFF

Apple Watch S5 (40mm, GPS) for $299.99

If you're shopping for a cellular model, there are also a few solid discounts on Amazon for these devices. You can get the Gold Aluminum Case with Pink Sport Band (40mm) for $399.00, down from $499.00. Likewise, the Silver Aluminum Case with White Sport Band (40mm) is $399.00 right now.

For the 44mm cellular models, a solid deal is the Space Gray Aluminum Case with Black Sport Band at $429.00, down from $529.00. You'll find the same price on the Silver Aluminum Case with White Sport Band and the Gold Aluminum Case with Pink Sport Band.

Across the board, these sales are either new low prices on the Apple Watch Series 5, or they're matching previous low prices seen on these models on Amazon. There are a few other deals going on for different Series 5 models as well, including numerous 44mm cellular devices that are about $50 off Apple's original prices. Be sure to head to Amazon to check out the full sale before these prices expire, or the retailer runs out of stock.

Keep up with all of this week's best discounts on Apple products and related accessories in our dedicated Apple Deals roundup.
This article, "Deals: Apple Watch Series 5 Models Discounted by Up to $100 on Amazon" first appeared on MacRumors.com

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Apple's plan to release an updated version of AirPods later this year has been delayed due to the global health crisis, according to the Nikkei Asian Review.


This lines up with a recent report from analyst Ming-Chi Kuo, who said that mass production of third-generation AirPods will begin in the first half of 2021, followed by mass production of second-generation AirPods Pro between the fourth quarter of 2021 and the first quarter of 2022. Kuo also expects Apple's rumored high-end over-ear headphones to enter mass production at some point in mid-2020.

Kuo did acknowledge rumors of new AirPods coming in the second half of 2020, but he said they are "more likely to be the new Beats model." Last month, leaker Jon Prosser claimed that Apple was planning to release so-called "AirPods X" around September or October with a BeatsX-like design for sports and running.

Apple's second-generation AirPods launched in March 2019, while the AirPods Pro were released at the end of October.

This article, "Apple's Plan to Introduce New AirPods Later This Year Reportedly Delayed" first appeared on MacRumors.com

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As governments restrict gatherings of people, furry conventions are being postponed or canceled. Here's a quick run down of events in April, May, and June and their status as of May 5 17:28 EDT (UTC-4) in response to the COVID-19 pandemic - updates to come.

A new section has been added for past events impacted for historical purposes.

Links go to statements if available, or to their Twitter feed or site. See also: Furry Fandom and the Internet forced back to roots by viral outbreak

read more

Pleased as hell to announce that the Fizzybees have released our first album, Hello World! You can stream it at Spotify and Soundcloud and iTunes and Google Play and all the usual places. If you’d like to download the mp3s, you can do so for free over at Bandcamp. We hope you have half as … Continue reading Hello World

Mele was my buddy. Mele was a very good dog. I love you, buddy. You run on ahead. We’ll be there to throw the ball for you soon enough.

— seeya soon, boring details about today’s comic: made with:

Erowid Exp113948

Erowid Exp114340

Erowid Exp108047

On the Young Turks, Cenk Uygur quotes passages from Bob Woodward's book, "The Price of Politics", quoting statements made by President Obama proving that he intends to cut entitlements like social security, medicare, and medicaid. Continue reading →

Cornel West and Tavis Smiley criticize President Barack Obama for being to the right of even President Richard Nixon. Continue reading →

Is your standard charge for a speech $300,000?  According to an article appearing on the website of the Las Vegas Review-Journal, and a May 31, 2013 email, Clinton’s standard contract usually includes: Round-trip transportation on a chartered private jet “e.g., a Gulfstream … Continue reading →

Online criminals have been systematically targeting TurboTax, filing fraudulent tax returns of individuals, and diverting their tax refunds to prepaid debit, cards, stealing their personal information, and using and impairing their credit ratings. Continue reading →

Democratic presidential candidate Bernie Sanders (I-VT) on Tuesday unveiled a plan to address income inequality by taxing Wall Street speculation and using the money to eliminate college tuition. Continue reading →

Presidential candidate Bernie Sanders says he wants to offer tuition free at public colleges and universities, paid for with a new tax on Wall Street. Ed Schultz and Sanders discuss the senator’s proposal. Continue reading →

Video and transcript of Farron Cousins' discussion of Hillary Clinton's fake populism on Ring of Fire TV, May 18, 2015. Continue reading →

Have you ever observed the mating dance of the birds of paradise? The male moves dramatically, and in response, the female inches away, but ultimately the male conquers the female, and achieves the purpose of this ritualistic, instinctive dance. Well, … Continue reading →

Chuck Todd tells Andrea Mitchell that Hillary Clinton will win the African-American and Hispanic vote in spite of the intellectual appeal of Bernie Sanders to liberal white voters Continue reading →

"This is supposed to be a political party. In a healthy society, there would be a democratic process in the Democratic Party, by which elected people would be overseeing these issues by making sure there wasn’t just nepotism and insider dealing," Curry says. "That the political party itself — which is supposed to be the progressive party — has become mortgaged to a small group of Washington insiders, who raise money from large corporate PACs, [and] has become just a dead carcass of what it once was, is the most important piece of information that this contretemps over the data files has emphasized. It’s time for progressives in this country to stand up and demand a genuinely democratic process." Continue reading →

Bernie Sanders would have already won this nominating contest if we had received an accurate accounting of the vote. It is deeply troubling the Senator would be sending out surrogates to talk about his allegiance to the Democratic party and Clinton in general in the face of the Party instituting theft against its own constituents. It is no mystery HOW to win. Count the votes and contest fraud. A tough Sane Progressive call out. Continue reading →

The evidence is adding up that this election is a SHAM! Exit polls do not add up on the Democratic side and regularly predict better results for Bernie than the voting machines are telling us! The mainstream media won't even come close to touching this, and in fact they're even attacking Lee Camp for bringing it up. Don't miss this segment of Redacted Tonight! Continue reading →

Bernie Sanders and Jane Sanders are mere actors serving as pressure valves which release from time to time all excess heat emanating from failed policies, scandals, and the worsening economic conditions, so that a catastrophic systems’ collapse can be prevented. They are sheepdogs for Hillary Clinton, preventing progressives from supporting a third party progressive candidate and to herd them back into the corral of the Democratic Party. Continue reading →

Noor asks Hedges how the presidential nominees should respond to these types of terrorist attacks in the U.S. “Their response should be the end of the occupation in the Middle East and the cessation of saturation bombing by drones and military aircrafts and missiles in parts of Iraq and Syria and Pakistan and Yemen and Somalia,” Hedges responds. He goes on to explain how decades of foreign policy decisions made by both parties have created the circumstances for terrorist attacks. Continue reading →

The middle class needs to vote for Donald Trump in order to oppose the elites, Corporate America, Wall Street, the career politicians, and the media, who have all conspired to destroy the middle class. Donald Trump is the Molotov cocktail, the human hand grenade, that every beaten-down, nameless, forgotten working stiff who used to be part of what was called the middle class can legally throw into the system that stole their lives from them. Continue reading →

"Trump didn’t hijack the populism, the Democratic Party made a gift of it to him. And he simply accepted it. … that elite … made a decision that in the midst of a global insurrection against political corruption and economic oligarchy that Hillary Clinton’s 'pay to play' politics in global finance capitalism would somehow play better than Bernie Sanders Democratic Socialism. … they ignored every poll they had, all the data they had, and even all the anecdotes they could possibly have accumulated in order to reach the conclusion that Hillary was a stronger candidate than Bernie. … And I remain certain that if anyone other than Clinton - and certainly if you accept for just one moment that when all the polls said the right things by such wide margins for so long they might be right - Bernie Sanders could have won this had he been the nominee, like Roosevelt took out Landon." Continue reading →

Donald Trump sold out his supporters and the 99% by selecting Wall Streeters and war mongers for his top cabinet positions. Continue reading →

This is the natural progression, this is the natural endgame of the Bill Clinton Democratic Party when he decided to change the Democratic Party from a party of workers and blue-collar people to a party of Silicon Valley and Wall Street. And Democrats have to acknowledge that. And if they don't, they ain't going nowhere. Continue reading →

Jimmy Dore: The intelligence agencies have been releasing the reports to convince us that we should be upset at Russia because they hacked our election. First of all, who gives a shit if they did? The United States tapped Angela Merkel’s … Continue reading →

The Democratic National Committee is controlled by its big corporate donors. Tom Perez was recruited to defeat progressive Keith Ellison to keep the Democratic Party in the coffers of its corporate donors. Ellison's defeat as head of the DNC was a hit job by the corporate machine within the DNC. Continue reading →

NEWS 8 IS YOUR LOCAL ELECTION HEADQUARTERS…. AND TONIGHT…VOODOO ECONOMICS! CHIEF POLITICAL CORRESPONDENT MARK DAVIS TELLING US HOW REPEALING THE STATE INCOME TAX IS THE LATEST HEATED TOPIC BETWEEN THE CANIDATES FOR GOVERNOR.   DEMOCRAT NED LAMONT IS OPENING A … Continue reading →

Tucker Carlson: Elizabeth Warren's enemies on Wall Street and Big Tech are not really her enemies. Elizabeth Warren is really just this season's Hillary Clinton -- faithful party robot, stalwart defender of the prerogatives of the establishment. Continue reading →

4GB USB Memory Stick in Cyan

Группа ELLEFSON, в состав которой входит басист MEGADETH DAVID ELLEFSON, представили собственное прочтение композиции POST MALONE “Over Now”, а с пятнадцатого мая этот трек появится на всех цифровых площадках. Этот трек будет включен в новый альбом, выход которого предварительно намечен на октябрь. #David_Ellefson #DavidEllefson

Criminal Minds newcomer Damon Gupton (Stephen Walker) celebrated his birthday yesterday, January 4. He was born on that day in 1973. Here...

Elecia and Chris of Embedded.fm invited us to come back on the show for episode 317: WHAT DO YOU MEAN BY DISINTEGRATED?. We also had the added enticement of a low tide adventure after recording. Lenore had been on the show back in 2014 for episode 40: MWAHAHA SESSION, and Windell was on the following … Continue reading Windell and Lenore on the Embedded.fm podcast →