This month Visa Europe announced its expansion of V.me, a digital wallet service which will be available to the majority of internet shoppers in the UK before the end of 2015. V.me launched in 2013 following a surge in the use of smartphones and tab...

(MENAFN - CDN Newswire) [To enable links in your articles, contact MENAFN Click here ] aims to cover market size, share, trends, and growth analysis... ......

The mayor of the western Turkish town of İznik, which is a key venue in the history of Christianity, has launched a campaign against those who paint the historic city walls with graffiti despite repeated warnings. Click through for the story in photos...

Samuel Murithi’s decision to grow the niche crops pays off as demand for the two vegetables picks up, thanks to their health benefits

A Hong Kong decorator who suffered a loss of income during anti-government protests was sentenced to four months’ jail for attacking a man following a row over posting messages on a so-called Lennon Wall last year.Kwun Tong Court heard that around 10pm on August 26, Hui Ching-ngai engaged in a heated argument with Ho Chin-leng, who saw Hui tearing down posters from a Lennon Wall inside a pedestrian tunnel in Tseung Kwan O.Hui, 39, who was drunk, picked up a broom and an umbrella from the ground…

Hong Kong police arrested 10 people following a fight between two groups with different political views at the so-called Lennon Wall in Wong Tai Sin district in the early hours of Friday.Five victims aged between 20 and 44 suffered injuries to their heads, backs and limbs in the incident that happened at a public housing estate in Lok Fu shortly before 12.30am.The dispute first erupted when a group of about 20 people carrying handy tools and paint were seen removing messages at the Lok Fu…

U.S. stocks closed higher Thursday as investors appeared more optimistic about an economic recovery. The Dow Jones industrial average, S&P 500 and Nasdaq Composite Index were all up 1 percent.  For the tech-heavy Nasdaq, Thursday's close put it back in positive territory for the first time ...

Stocks on Wall Street jumped Friday despite historic job losses suffered by the economy. Fred Katayama reports.

Olivia Colman and Helen Mirren have teamed up with the creators of Wallace & Gromit in a film called Turtle Journey to raise awareness about climate change and ocean pollution

Vast machines have left the subterranean world of a potash mine in the Urals with ammonite-like whorls, photographed for a project to highlight lasting human impacts on the planet.

Olivia Colman and Helen Mirren have teamed up with the creators of Wallace & Gromit in a film called Turtle Journey to raise awareness about climate change and ocean pollution

Goldman Sachs shareholders gave lukewarm approval for CEO David Solomon’s $27.5 mln package. It’s similar to what his peers get, and most of it doesn’t come for at least a year. Still, in a time of economic crisis, eight-digit rewards attract extra scrutiny, John Foley suggests.

Shanghai Auto Show 2019 – SHANGHAI – April 16, 2019 – HARMAN , a wholly-owned subsidiary of Samsung Electronics Co., Ltd., focused on connected technologies for automotive, consumer and enterprise markets, today announced a continued partnership with the...

Stocks on Wall Street jumped Friday despite historic job losses suffered by the economy. Fred Katayama reports.

ABSTRACT

The Candida albicans high-affinity phosphate transporter Pho84 is required for normal Target of Rapamycin (TOR) signaling, oxidative stress resistance, and virulence of this fungal pathogen. It also contributes to C. albicans’ tolerance of two antifungal drug classes, polyenes and echinocandins. Echinocandins inhibit biosynthesis of a major cell wall component, beta-1,3-glucan. Cells lacking Pho84 were hypersensitive to other forms of cell wall stress beyond echinocandin exposure, while their cell wall integrity signaling response was weak. Metabolomics experiments showed that levels of phosphoric intermediates, including nucleotides like ATP and nucleotide sugars, were low in pho84 mutant compared to wild-type cells recovering from phosphate starvation. Nonphosphoric precursors like nucleobases and nucleosides were elevated. Outer cell wall phosphomannan biosynthesis requires a nucleotide sugar, GDP-mannose. The nucleotide sugar UDP-glucose is the substrate of enzymes that synthesize two major structural cell wall polysaccharides, beta-1,3- and beta-1,6-glucan. Another nucleotide sugar, UDP-N-acetylglucosamine, is the substrate of chitin synthases which produce a stabilizing component of the intercellular septum and of lateral cell walls. Lack of Pho84 activity, and phosphate starvation, potentiated pharmacological or genetic perturbation of these enzymes. We posit that low substrate concentrations of beta-d-glucan- and chitin synthases, together with pharmacologic inhibition of their activity, diminish enzymatic reaction rates as well as the yield of their cell wall-stabilizing products. Phosphate import is not conserved between fungal and human cells, and humans do not synthesize beta-d-glucans or chitin. Hence, inhibiting these processes simultaneously could yield potent antifungal effects with low toxicity to humans.

IMPORTANCE Candida species cause hundreds of thousands of invasive infections with high mortality each year. Developing novel antifungal agents is challenging due to the many similarities between fungal and human cells. Maintaining phosphate balance is essential for all organisms but is achieved completely differently by fungi and humans. A protein that imports phosphate into fungal cells, Pho84, is not present in humans and is required for normal cell wall stress resistance and cell wall integrity signaling in C. albicans. Nucleotide sugars, which are phosphate-containing building block molecules for construction of the cell wall, are diminished in cells lacking Pho84. Cell wall-constructing enzymes may be slowed by lack of these building blocks, in addition to being inhibited by drugs. Combined targeting of Pho84 and cell wall-constructing enzymes may provide a strategy for antifungal therapy by which two sequential steps of cell wall maintenance are blocked for greater potency.

ABSTRACT

The wall teichoic acid (WTA) is a major cell wall component of Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), a common cause of fatal clinical infections in humans. Thus, the indispensable ABC transporter TarGH, which flips WTA from cytoplasm to extracellular space, becomes a promising target of anti-MRSA drugs. Here, we report the 3.9-Å cryo-electron microscopy (cryo-EM) structure of a 50% sequence-identical homolog of TarGH from Alicyclobacillus herbarius at an ATP-free and inward-facing conformation. Structural analysis combined with activity assays enables us to clearly decode the binding site and inhibitory mechanism of the anti-MRSA inhibitor Targocil, which targets TarGH. Moreover, we propose a "crankshaft conrod" mechanism utilized by TarGH, which can be applied to similar ABC transporters that translocate a rather big substrate through relatively subtle conformational changes. These findings provide a structural basis for the rational design and optimization of antibiotics against MRSA.

IMPORTANCE The wall teichoic acid (WTA) is a major component of cell wall and a pathogenic factor in methicillin-resistant Staphylococcus aureus (MRSA). The ABC transporter TarGH is indispensable for flipping WTA precursor from cytoplasm to the extracellular space, thus making it a promising drug target for anti-MRSA agents. The 3.9-Å cryo-EM structure of a TarGH homolog helps us to decode the binding site and inhibitory mechanism of a recently reported inhibitor, Targocil, and provides a structural platform for rational design and optimization of potential antibiotics. Moreover, we propose a "crankshaft conrod" mechanism to explain how a big substrate is translocated through subtle conformational changes of type II exporters. These findings advance our understanding of anti-MRSA drug design and ABC transporters.

Programmed death-ligand 1 (PD-L1/B7-H1) serves as a cosignaling molecule in cell-mediated immune responses and contributes to chronicity of inflammation and the escape of tumor cells from immunosurveillance. Here, we investigated the molecular mechanisms leading to PD-L1 upregulation in human oral carcinoma cells and in primary human gingival keratinocytes in response to infection with Porphyromonas gingivalis (P. gingivalis), a keystone pathogen for the development of periodontitis. The bacterial cell wall component peptidoglycan uses bacterial outer membrane vesicles to be taken up by cells. Internalized peptidoglycan triggers cytosolic receptors to induce PD-L1 expression in a myeloid differentiation primary response 88 (Myd88)-independent and receptor-interacting serine/threonine-protein kinase 2 (RIP2)-dependent fashion. Interference with the kinase activity of RIP2 or mitogen-activated protein (MAP) kinases interferes with inducible PD-L1 expression.

BACKGROUND AND PURPOSE:

Not all tandem occlusions diagnosed on traditional vascular imaging modalities, such as MRA, represent actual complete ICA occlusion. This study aimed to explore the utility of high-resolution vessel wall imaging in identifying true ICA tandem occlusions and screening patients for their suitability for endovascular recanalization.

BACKGROUND AND PURPOSE:

Vessel wall imaging is increasingly performed in the diagnostic work-up of patients with ischemic stroke. The aim of this study was to compare vessel wall enhancement after intra-arterial thrombosuction with that in patients not treated with thrombosuction.

The U.S. government reported more catastrophic economic fallout from the coronavirus crisis on Friday as the pandemic pierced the very walls of the White House and California gave the green light for its factories to restart after a seven-week lockdown.

Hundreds of workers pass through Ajo, Arizona, daily. Residents say they have been partying and visiting stores in large groups

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Unlike the rest of the US, the sleepy border community of Ajo, Arizona, is busier than ever these days, as hundreds of border wall construction workers pass through each day.

“The rest of us are staying at home just the way the governor has ordered,” said Susan Guinn-Lahm, an Ajo resident in her 60s. “We’re taking this seriously. They are not.”

Major U.S. stock indexes jumped on Friday and logged solid gains for the week after data on historic job losses due to the coronavirus crisis showed they were slightly fewer than feared.

A week packed with U.S. economic data is likely to provide investors with more evidence of the extent to which the coronavirus pandemic has hit growth, sharpening the debate on whether a rebound in stocks has been justified amid an unprecedented slowdown.

The Duchess of Cornwall has revealed she has taken up ballet and is practising her poses and positions to keep fit in lockdown.

Police have launched an investigation after 23 cows and calves were reported missing from a farm in Cornwall.

In a bustling depot in north London filled with donated food, Phoebe Waller-Bridge compared the work of The Felix Project to "a rescue mission".

Earth's closest black hole has been discovered by astronomers and it is big enough to swallow the whole of Washington DC.

Consumers are starting to see meat shortages after thousands of workers fall ill.

Yep, in-the-wild SQL injection exploits in 2020 are still a thing.

The pair will reunite for BBC's 'Big Night In'

Writer and creator of the hit show recalled the moment a delivery driver was confronted with it

A new kind of survival story: Scientists discovered a star that came near a black hole and lived to tell the tale – at least temporarily.

The Quiz star says she still feels like she constantly has to prove herself as an actor

Millwall have decided against furloughing their squad because players would be unable to follow club training programmes while on leave.

The Australian racing industry is in turmoil after revelations of former racehorses being slaughtered at abattoirs, with leading trainer Chris Waller so shocked he "couldn't watch" the vision.