As schools and businesses get set to reopen some citizens urge caution, wary of a spike in infections

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France is set to end eight weeks of strict lockdown as the government urged people to behave responsibly to avoid a sudden spike in coronavirus cases.

Hours before the national déconfinement there were reports of two new Covid-19 clusters in départments designated green – areas where the virus has largely stopped circulating and where most restrictions are being lifted.

No one should be complacent about racism but the story is rarely as straightforward as some commentators routinely assert

In my city neighbourhood this summer a man on the run from police custody hit a black woman in the face. Understandably, she reported it as a racial attack. Except it probably wasn’t. The runaway also hit a boy when his mother opened the door and tried to spray another woman’s hair red at a bus stop. He had mental health problems.

Not much harm done in this instance. But it’s one reason why I don’t often write about race relations in modern Britain, though I first did so 50 years ago when many aspects of them were pretty grim.

Emigration from hurricane-hit island is likely to be centred on New York and Florida

Diversifying the portfolio of candidates is one of the most important steps

England stars Maro Itoje and Mako Vunipola are yet to commit to playing for Saracens in the Championship next season. Two French clubs have already expressed interest in Itoje.

The state-owned airline, which suspended regular passenger flights in March reported a 21% rise in profit for its financial year that ended on March 31

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The Sensational Grace Hotel, Santorini Islands

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Tottenham are ahead of Manchester United in the race for Thomas Meunier, Real Madrid want Aubameyang decision, plus more.

Mercedes' Lewis Hamilton has said that holding races without any fans will feel "even worse than a test day".

Former New Zealand head coach and current England defence chief John Mitchell believes some good may come for rugby union from the coronavirus.

Prevention of aberrant cutaneous wound repair and appropriate regeneration of an intact and functional integument require the coordinated timing of fibroblast and keratinocyte migration. Here, we identified a mechanism whereby opposing cell-specific motogenic functions of a multifunctional intracellular and extracellular protein, the receptor for hyaluronan-mediated motility (RHAMM), coordinates fibroblast and keratinocyte migration speed and ensures appropriate timing of excisional wound closure. We found that, unlike in WT mice, in Rhamm-null mice, keratinocyte migration initiates prematurely in the excisional wounds, resulting in wounds that have re-surfaced before the formation of normal granulation tissue, leading to a defective epidermal architecture. We also noted aberrant keratinocyte and fibroblast migration in the Rhamm-null mice, indicating that RHAMM suppresses keratinocyte motility but increases fibroblast motility. This cell context–dependent effect resulted from cell-specific regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and expression of a RHAMM target gene encoding matrix metalloprotease 9 (MMP-9). In fibroblasts, RHAMM promoted ERK1/2 activation and MMP-9 expression, whereas in keratinocytes, RHAMM suppressed these activities. In keratinocytes, loss of RHAMM function or expression promoted epidermal growth factor receptor–regulated MMP-9 expression via ERK1/2, which resulted in cleavage of the ectodomain of the RHAMM partner protein CD44 and thereby increased keratinocyte motility. These results identify RHAMM as a key factor that integrates the timing of wound repair by controlling cell migration.

Inter-α-inhibitor is a proteoglycan essential for mammalian reproduction and also plays a less well-characterized role in inflammation. It comprises two homologous “heavy chains” (HC1 and HC2) covalently attached to chondroitin sulfate on the bikunin core protein. Before ovulation, HCs are transferred onto the polysaccharide hyaluronan (HA) to form covalent HC·HA complexes, thereby stabilizing an extracellular matrix around the oocyte required for fertilization. Additionally, such complexes form during inflammatory processes and mediate leukocyte adhesion in the synovial fluids of arthritis patients and protect against sepsis. Here using X-ray crystallography, we show that human HC1 has a structure similar to integrin β-chains, with a von Willebrand factor A domain containing a functional metal ion-dependent adhesion site (MIDAS) and an associated hybrid domain. A comparison of the WT protein and a variant with an impaired MIDAS (but otherwise structurally identical) by small-angle X-ray scattering and analytical ultracentrifugation revealed that HC1 self-associates in a cation-dependent manner, providing a mechanism for HC·HA cross-linking and matrix stabilization. Surprisingly, unlike integrins, HC1 interacted with RGD-containing ligands, such as fibronectin, vitronectin, and the latency-associated peptides of transforming growth factor β, in a MIDAS/cation-independent manner. However, HC1 utilizes its MIDAS motif to bind to and inhibit the cleavage of complement C3, and small-angle X-ray scattering–based modeling indicates that this occurs through the inhibition of the alternative pathway C3 convertase. These findings provide detailed structural and functional insights into HC1 as a regulator of innate immunity and further elucidate the role of HC·HA complexes in inflammation and ovulation.

β-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide. Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form β-cholesterylglucoside (β-GlcChol) in vitro. β-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate β-GlcChol metabolism in the brain is unknown. Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (β-GalChol), in addition to β-GlcChol. Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for β-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for β-GalChol formation. Liquid chromatography–tandem MS revealed that β-GlcChol and β-GalChol are present throughout development from embryo to adult in the mouse brain. We found that β-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of β-GalChol biosynthesis appeared to be during myelination. We also found that β-GlcChol and β-GalChol are secreted from neurons and glial cells in association with exosomes. In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form β-GalChol. This is the first report of the existence of β-GalChol in vertebrates and how β-GlcChol and β-GalChol are formed in the brain.

Lens proteins become increasingly cross-linked through nondisulfide linkages during aging and cataract formation. One mechanism that has been implicated in this cross-linking is glycation through formation of advanced glycation end products (AGEs). Here, we found an age-associated increase in stiffness in human lenses that was directly correlated with levels of protein–cross-linking AGEs. α-Crystallin in the lens binds to other proteins and prevents their denaturation and aggregation through its chaperone-like activity. Using a FRET-based assay, we examined the stability of the αA-crystallin–γD-crystallin complex for up to 12 days and observed that this complex is stable in PBS and upon incubation with human lens–epithelial cell lysate or lens homogenate. Addition of 2 mm ATP to the lysate or homogenate did not decrease the stability of the complex. We also generated complexes of human αA-crystallin or αB-crystallin with alcohol dehydrogenase or citrate synthase by applying thermal stress. Upon glycation under physiological conditions, the chaperone–client complexes underwent greater extents of cross-linking than did uncomplexed protein mixtures. LC-MS/MS analyses revealed that the levels of cross-linking AGEs were significantly higher in the glycated chaperone–client complexes than in glycated but uncomplexed protein mixtures. Mouse lenses subjected to thermal stress followed by glycation lost resilience more extensively than lenses subjected to thermal stress or glycation alone, and this loss was accompanied by higher protein cross-linking and higher cross-linking AGE levels. These results uncover a protein cross-linking mechanism in the lens and suggest that AGE-mediated cross-linking of α-crystallin–client complexes could contribute to lens aging and presbyopia.

The dextransucrase DSR-OK from the Gram-positive bacterium Oenococcus kitaharae DSM17330 produces a dextran of the highest molar mass reported to date (∼109 g/mol). In this study, we selected a recombinant form, DSR-OKΔ1, to identify molecular determinants involved in the sugar polymerization mechanism and that confer its ability to produce a very-high-molar-mass polymer. In domain V of DSR-OK, we identified seven putative sugar-binding pockets characteristic of glycoside hydrolase 70 (GH70) glucansucrases that are known to be involved in glucan binding. We investigated their role in polymer synthesis through several approaches, including monitoring of dextran synthesis, affinity assays, sugar binding pocket deletions, site-directed mutagenesis, and construction of chimeric enzymes. Substitution of only two stacking aromatic residues in two consecutive sugar-binding pockets (variant DSR-OKΔ1-Y1162A-F1228A) induced quasi-complete loss of very-high-molar-mass dextran synthesis, resulting in production of only 10–13 kg/mol polymers. Moreover, the double mutation completely switched the semiprocessive mode of DSR-OKΔ1 toward a distributive one, highlighting the strong influence of these pockets on enzyme processivity. Finally, the position of each pocket relative to the active site also appeared to be important for polymer elongation. We propose that sugar-binding pockets spatially closer to the catalytic domain play a major role in the control of processivity. A deep structural characterization, if possible with large-molar-mass sugar ligands, would allow confirming this hypothesis.

Bacterial biofilms are cellular communities that produce an adherent matrix. Exopolysaccharides are key structural components of this matrix and are required for the assembly and architecture of biofilms produced by a wide variety of microorganisms. The human bacterial pathogens Escherichia coli and Salmonella enterica produce a biofilm matrix composed primarily of the exopolysaccharide phosphoethanolamine (pEtN) cellulose. Once thought to be composed of only underivatized cellulose, the pEtN modification present in these matrices has been implicated in the overall architecture and integrity of the biofilm. However, an understanding of the mechanism underlying pEtN derivatization of the cellulose exopolysaccharide remains elusive. The bacterial cellulose synthase subunit G (BcsG) is a predicted inner membrane–localized metalloenzyme that has been proposed to catalyze the transfer of the pEtN group from membrane phospholipids to cellulose. Here we present evidence that the C-terminal domain of BcsG from E. coli (EcBcsGΔN) functions as a phosphoethanolamine transferase in vitro with substrate preference for cellulosic materials. Structural characterization of EcBcsGΔN revealed that it belongs to the alkaline phosphatase superfamily, contains a Zn2+ ion at its active center, and is structurally similar to characterized enzymes that confer colistin resistance in Gram-negative bacteria. Informed by our structural studies, we present a functional complementation experiment in E. coli AR3110, indicating that the activity of the BcsG C-terminal domain is essential for integrity of the pellicular biofilm. Furthermore, our results established a similar but distinct active-site architecture and catalytic mechanism shared between BcsG and the colistin resistance enzymes.

Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion of autophagy-related 5 (ATG5), results in accumulation of intracellular VEGFA, indicating that VEGFA is a basal autophagic substrate. Mechanistically, decorin increased the VEGFA clearance rate by augmenting autophagic flux, a process that required RAB24 member RAS oncogene family (RAB24), a small GTPase that facilitates the disposal of autophagic compartments. We validated these findings by demonstrating the physiological relevance of this process in vivo. Mice starved for 48 h exhibited a sharp decrease in overall cardiac and aortic VEGFA that could be blocked by systemic chloroquine treatment. Thus, our findings reveal a unified mechanism for the metabolic control of endothelial VEGFA for autophagic clearance in response to decorin and canonical pro-autophagic stimuli. We posit that the VEGFR2/AMPK/PEG3 axis integrates the anti-angiogenic and pro-autophagic bioactivities of decorin as the molecular basis for tumorigenic suppression. These results support future therapeutic use of decorin as a next-generation protein therapy to combat cancer.

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.

God uses bracelets to weave together a group of children from different cultures and backgrounds so they can experience His love.

By Deborah Anderson

As the Bus4Life begins its seventh tour, former driver Tuukka Linkopuu reflects on his two-year ministry while Esa Tuuri prepares to take the wheel.

Over a thousand people visited the medical clinic that OM Ecuador recently installed in the small town of Cadeate. Many also came to faith.

The Bajaj Pulsar 125 BS6 is costlier by Rs 6,000 but retains its class leading power and torque outputs.

TVS' fantastic-looking flagship - the Apache RR 310 has got an important update for 2019 that should keep a lot of customers happy! Here, in this comprehensive review, we tell you how the new version is to ride and what all has changed, for the good or bad!

A "dark horse" is defined as a little-known entity that emerges to prominence in the face of competition — a contestant that seems unlikely to succeed. I borrow the term from a conversation last week, wherein India was referred to as the dark horse in the global race to go solar.

The race for renewable energy has passed a turning point. The world is now adding more capacity for renewable power each year than coal, natural gas, and oil combined. And there's no going back.

The World Bank indicated in its new report "Building Competitive Green Industries: The Climate and Clean Technology Opportunity for Developing Countries" that small and medium-sized enterprises (SMEs) in developing countries are set to undergo significant growth and create more jobs in the field of clean technology. Anabel Gonzalez, senior director for the World Bank's Global Practice on Trade and Competitiveness, said developing home-grown clean-tech industries will help developing countries more effectively increase the adoption of low-cost clean energy and drive sustainable economic development.

RWE AG, the German utility whose coal-fired plants make it Europe’s largest carbon emitter, officially started the company’s largest renewables project on Thursday: a wind farm in Liverpool Bay off Britain’s coast.

Grace Millane's family has given hundreds of care packages to patients, nurses, doctors and carers battling coronavirus.The family of the murdered British backpacker has donated more than 300 bags full of toiletries to hospitals...

It has exposed the huge economic disparities in homes that enhance social inequalities.

Authorities acquire passenger manifest for the bus patient travelled in.

With high rates of alcoholism and drug abuse, communities try to address profound social ills

Team Sonnenwagen from RWTH Aachen University race in the Bridgestone World Solar Challenge, in Australia.

The Prime Minister Narendra Modi-led government is of the opinion that the negative image of China in the international community may help in getting investment worth Rs 25 lakh crore, if the cards are played well.

The Prime Minister Narendra Modi-led government is of the opinion that the negative image of China in the international community may help in getting investment worth Rs 25 lakh crore, if the cards are played well.

The Prime Minister Narendra Modi-led government is of the opinion that the negative image of China in the international community may help in getting investment worth Rs 25 lakh crore, if the cards are played well.

Belgian series is based on 2015 novel by Polish science fiction writer Jacek Dukaj

A trial of Britain's proposed coronavirus test-and-trace app being conducted on the Isle of Wight off the coast of southern England is going well, Transort Secretary Grant Shapps said on Saturday.

Daniel Ricciardo says Formula 1’s return will see ‘chaos’ in the opening race as drivers get back in the car for the first time after the coronavirus-enforced break.

Tune into our new show Fox League Live on Channel 502 Monday to Friday at 6.30pm and on Saturday at 3pm and Sunday at 5pm.

Lewis Hamilton says he's getting messages from fans desperate to see the return of Formula One, but the six-time world champion feels races without them will be "worse than a test day".

The crisis has also unearthed new opportunities for investors eyeing distressed hospitality and retail assets.

The post Southeast Asia’s realty market braces for short-term instability appeared first on DealStreetAsia.

Jenson Button is expecting to have a strong race at the Brazilian Grand Prix this weekend, but is hoping for rain on Saturday to mix up the qualifying order

Sam Michael was left to lament yet another problem filled race for the struggling Williams team in the Canadian Grand Prix

Virgin Racing technical director Nick Wirth was left reflecting on a 'worse-case scenario' of tyre degradation that hampered his team's chances at the Canadian Grand Prix

Renault technical director James Allison says the French team is capable of scoring points in every race of the season after Robert Kubica finished just outside the top 10 in Bahrain

A closer look at who did what at the Malaysian Grand Prix

Nick Wirth, Virgin Racing Technical Director, said that Lucas di Grassi's 14th place finish at the Malaysian Grand Prix was great reward for everyone involved with the team