Protease-activated receptor 2 (PAR-2) is activated by secreted proteases from immune cells or fungi. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. We hypothesized that epithelial remodeling during diseases characterized by cilial loss and squamous metaplasia may alter PAR-2 polarization. Here, using a fluorescent arrestin assay, we confirmed that the common fungal airway pathogen Aspergillus fumigatus activates heterologously-expressed PAR-2. Endogenous PAR-2 activation in submerged airway RPMI 2650 or NCI–H520 squamous cells increased intracellular calcium levels and granulocyte macrophage–colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-6 secretion. RPMI 2650 cells cultured at an air–liquid interface (ALI) responded to apically or basolaterally applied PAR-2 agonists. However, well-differentiated primary nasal epithelial ALIs responded only to basolateral PAR-2 stimulation, indicated by calcium elevation, increased cilia beat frequency, and increased fluid and cytokine secretion. We exposed primary cells to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency, at concentrations and times that altered epithelial morphology without causing breakdown of the epithelial barrier to model early disease states. These altered primary cultures responded to both apical and basolateral PAR-2 stimulation. Imaging nasal polyps and control middle turbinate explants, we found that nasal polyps, but not turbinates, exhibit apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyps and turbinates maintained basolateral PAR-2 polarization, suggesting that the calcium responses originated from nonciliated cells. Altered PAR-2 polarization in disease-remodeled epithelia may enhance apical responses and increase sensitivity to inhaled proteases.

Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan perlecan, influences various signaling pathways in endothelial cells by binding to VEGFR2. In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4, and GADD45α. Specifically, endorepellin evoked transient activation of VEGFR2, which, in turn, phosphorylated PERK at Thr980. Subsequently, PERK phosphorylated eIF2α at Ser51, upregulating its downstream effector proteins ATF4 and GADD45α. RNAi-mediated knockdown of PERK or eIF2α abrogated the endorepellin-mediated up-regulation of GADD45α, the ultimate effector protein of this stress signaling cascade. To functionally validate these findings, we utilized an ex vivo model of angiogenesis. Exposure of the aortic rings embedded in 3D fibrillar collagen to recombinant endorepellin for 2–4 h activated PERK and induced GADD45α vis à vis vehicle-treated counterparts. Similar effects were obtained with the established cellular stress inducer tunicamycin. Notably, chronic exposure of aortic rings to endorepellin for 7–9 days markedly suppressed vessel sprouting, an angiostatic effect that was rescued by blocking PERK kinase activity. Our findings unravel a mechanism by which an extracellular matrix protein evokes stress signaling in endothelial cells, which leads to angiostasis.

State-of-the-art electron microscopy reveals the large-scale organization of the proteins that regulate neurotransmitter release

This spectacular image – which took the best part of a year to create – shows the fine structure of a nerve terminal at high resolution, revealing, for the very first time, an intricate network of fine filaments that controls the movements of synaptic vesicles.

The brain is soft and wet, with the consistency of a lump of jelly. Yet, it is the most complex and highly organized structure that we know of, containing hundreds of billions of neurons and glial cells, and something on the order of one quadrillion synaptic connections, all of which are arranged in a very specific manner.

Related: 3D model of a nerve terminal in atomic detail | Mo Costandi

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Testimony of Marc R. Rosenblum, Deputy Director, U.S. Immigration Program, before the House Committee on Homeland Security Subcommittee on Oversight and Management Efficiency.

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The scientists tested their vaccine on mice. The mice developed antibodies immediately after a single injection, which prevented the virus from infecting human cells. Researchers selected 2 of the five candidates for the vaccine after studying them with the best results.

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The brand has released a new television commercial featuring the actor

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Cadence is hosting a Front End Design Summit on Thursday, December 6, 2012 9:30am – 5:00pm at Cadence San Jose headquarters, 2655 Seely Avenue, Building 10. Logic designers will hear from customers including Cisco, Chelsio, PMC, Spansion, and Via Technologies...(read more)

Anomalous Payloadbased Worm Detection and Signature Generation.

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Coal is having a hard time lately. U.S. power plants are switching to natural gas, environmental restrictions are kicking in, and the industry is being derided as the world's No. 1 climate criminal. Prices have crashed, sure, but for a real sense of coal's diminishing prospects, check out what's happening in the bond market.

The G20 meeting in Hangzhou, China, this September brings together leaders of the world’s largest economies for the first such gathering since the 2015 Paris Agreement on climate. G20 Leaders Summits traditionally focus on economic growth and financial stability, but since more than 190 countries collectively agreed to greatly enhance mitigation of the causes and impacts of climate change, the need to tackle a changing climate and foster clean energy has become a clear economic and business reality.

Having inherited the Agency Workers Regulations 2010 on taking office, the UK Government had pledged to review them. That process is now underway but it seems the EU may pip the Government to the post, having conducted its own review of the parent D...

Precis Having inherited the Agency Workers Regulations 2010 on taking office, the UK Government had pledged to review them. That process is now underway but it seems the EU may pip the Government to the post, having conducted its own review of the ...

Palo Alto, CA – Aha by HARMAN™ today announced that the new 2014 Mazda3to be launched in North America and Europethis fall will offer access to Aha's free service withthe ability to select presets from more than 40,000* audio and information stations.

The design of an eLearning game is critical to its effectiveness. Keeping learners engaged and involved is key to learning success.

The post The Key to Engaging Learners: Designing Effective eLearning Games appeared first on e-Learning Feeds.

Rep. Dana Rohrabacher (R-Calif.) won his first election to the House of Representatives in 1988 with 64 percent of the vote. He's been reelected 13 times since then. And even though he walloped his most recent challenger by nearly 17 percentage points, some Democrats now think that this could be the final term for the Southern California conservative Politico has dubbed "Putin's favorite congressman."

Protesters, sometimes numbering in the hundreds, assemble outside Rohrabacher's office every Tuesday at 1 p.m. "He has been our congressman for a long time," laments Diana Carey, vice chair of the Democratic Party of Orange County. "But because the district was predominantly Republican, my view is he's been on cruise control." Thanks to changing demographics in Orange County and newly fired-up liberal voters, Carey doesn't think Rohrabacher's seat is safe anymore. 

Recently, Rohrabacher has been swept up in the scandal over the possible collusion between President Donald Trump's campaign and Russia. Like Trump, Rohrabacher, who claims to once have lost a drunken arm-wrestling match with Vladimir Putin in the 1990s, believes the Russian government is being unfairly demonized. (During the 1980s, Rohrabacher was a staunch anti-communist who hung out with the anti-Soviet mujahedeen in Afghanistan.) He has shrugged off allegations of Moscow's meddling in the 2016 presidential election by pointing out that the United States is guilty of similar actions. In May, the New York Times reported that in 2012 the FBI warned Rohrabacher that Russian spies were trying to recruit him. Two days earlier, the Washington Post reported on a recording from June 2016 in which House Majority Leader Kevin McCarthy said, "There's two people I think Putin pays: Rohrabacher and Trump." (McCarthy assured Rohrabacher the remarks were meant as a joke.)

But of all the issues where Rohrabacher and Trump align, Russia may be the least pressing concern for the constituents who are rallying against him. So far, Rohrabacher has voted in line with Trump's positions more than 93 percent of the time, according to FiveThirtyEight, including voting in favor of the GOP health care bill that would effectively end Obamacare. Rohrabacher pushed hard for the bill, warning his GOP colleagues that letting Trump's first major legislative effort die would stunt the president's momentum. "If this goes down," he said in March, "we're going to be neutering our President Trump. You don't cut the balls off your bull and expect that's he's going to go out and get the job done." Health care is a hot-button issue in the 48th District, Carey says. "I've had conversations with people who are absolutely beside themselves, scared that they're going to lose coverage."

While Rohrabacher won his last race in a near-landslide, his district went for Hillary Clinton in the presidential election. She won by a slim margin, but it was enough for the Democratic Congressional Campaign Committee (DCCC) to flag the district as a top target to flip in 2018. If the Democrats hope to best Rohrabacher in the midterms, they have a lot of work to do, says Justin Wallin, an Orange County-based pollster who runs an opinion research firm. "I don't think Dana has carved out a position as a fire-breathing supporter for any political personality except for Ronald Reagan," says Wallin, referring to Rohrabacher's early days working in the Reagan White House. "He tends to align quite naturally with that district in his perspectives, his persona, and his political views. His district views him as being independent, and when Dana takes a position on something that seems to be outside the mainstream, that can actually buttress his favorable regard."

Two Democrats have announced bids to run against Rohrabacher. One is first-time candidate Harley Rouda, a businessman and attorney who gave $9,200 to Republican congressional candidates and nothing to Democrats between 1993 and 2007. The other is Boyd Roberts, a Laguna Beach real estate broker who has vowed to work to impeach Trump and who finished last among five candidates running for a school board seat in Hemet, California, in 2012. Both are attacking Rohrabacher over his sympathetic stance toward Russia. "The district will vote [Rohrabacher] out because i think there is something with the Russia thing. I think I can raise money off it," Roberts told the Los Angeles Times. In an online ad, Rouda calls Rohrabacher "one of the most entrenched members of Washington's establishment" and vows to get "tough on Russia" if he is elected.

"They're both kind of waving the flag of the Russia thing, and I just don't think that's gonna get them over the line," says Wallin. Carey declined to comment on either candidate, though she says a third challenger will be announcing a bid this summer. Meanwhile, the DCCC hasn't thrown its backing behind anyone yet. "Barring something dramatic happening, I'd say he is far more safe than a number of other districts in the area," says Wallin.

Yet Carey thinks that so long as the Democrats continue organizing with the same intensity they've shown so far, they can turn the district blue. "We have a lot of folks who said they never paid attention before, a lot of no-party-preference people who are really concerned about democracy," she says. When asked whether people in the district continue to be engaged, she responds, "So far I think the energy is staying. I tell people, 'This is not a sprint, it's a marathon.' But I think as long as Trump keeps tweeting, we'll keep having interest!"

There has been a significant surge in contactless payments for everyday purchases since the onset of COVID-19, according to a new study. The Mastercard global consumer study conducted from April 10 to 12 says that in Canada, 76 per cent of consumers say contactless payments are now their preferred way to pay when making in-store…

Remote teaching tools from Keysight

Master signal integrity and ensure data quality

This pro-bono initiative crowdsourced 4,500 drug designs, synthesized 311, and is now testing them against viral proteins