missgingin:

This is a place I wouldn’t mind retire a long life at with someone I could never get tired of.

Check out travel recommendations at Wanderfly!

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mirorandderideo:

The Sensational Grace Hotel, Santorini Islands

Check out travel recommendations at Wanderfly!

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Investigators are using additional video footage to reconstruct the February afternoon that Ahmaud Arbery was fatally shot in a quiet southern Georgia neighborhood.

Investigators are using additional video footage to reconstruct the February afternoon that Ahmaud Arbery was fatally shot in a quiet southern Georgia neighborhood.

There was certainly was stress in the air when health and economic consqeuences of COVID-19 bore down on Brooklyn and the rest of America. But as these pressures grew, constructive hearts and minds prevailed at the BKLYN Commons (BKC) shared workspace operation at 495 Flatbush Ave., in the Prospect-Lefferts Gardens area, which creatively and passionately morphed to adapt to the new normal.

Purdue coach Matt Painter and staff will explore the July evaluation period over the next three weeks. But the recruiting foundation for 2019 is set.

Now you can read all of IndyStar's sports content in one place with our free INSports app.

The newly-created U.S. Space Force has released its first recruitment video, CNET reports: In a video posted Wednesday to Twitter showing rockets, mission control-types rooms and U.S. Space Force members in spacesuits, a voice-over says, "maybe your purpose on this planet isn't on this planet." Secretary of the Air Force Barbara Barrett said during a livestream Wednesday that so far recruitment hasn't been a problem for the Space Force. "There's been an avalanche of applicants." This sixth branch of the US military was established in December 2019 and will be operational by mid-2021. CNET notes the video appeared "a day after Netflix dropped a trailer for its upcoming comedy Space Force. And the leader of the U.S. Space Force says he's looking forward to the Netflix comedy co-created by Steve Carell. "The one piece of advice I'd give to Steve Carell is to get a haircut," Gen. Jay Raymond, the U.S. Space Force Chief of Space Operations, said Wednesday during a webinar hosted by the nonprofit Space Foundation. Raymond is bald, and joked that Steve Carell is "looking a little too shaggy if he wants to play the Space Force chief."

Read more of this story at Slashdot.

How a Typical Facebook Scam Works?

How a Typical Facebook Scam Works?

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

Filed under: Internet Tools, News

Continue reading Facebook, Instagram Release Top Checked-in Locations of 2013

Facebook, Instagram Release Top Checked-in Locations of 2013 originally appeared on Gadling on Fri, 13 Dec 2013 14:23:00 EST. Please see our terms for use of feeds.

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.

The following article, Professor Who Mocked Barron Trump During Senate Hearings Gets Censorship Position at Facebook, was first published on 100PercentFedUp.com.

Facebook just announced a 20 person board of oversight that will assist with content moderation. One of the people selected for the board, a professor at Stanford Law School, was announced as a member of the board and is raising eyebrows because of her snarky comment about Barron Trump during Senate Impeachment Hearings. Pamela Karlan, […]

Continue reading: Professor Who Mocked Barron Trump During Senate Hearings Gets Censorship Position at Facebook ...

Invitation Only Research Event

14 July 2016

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.

Contact between inflammatory cells and endothelial cells (ECs) is a crucial step in vascular inflammation. Recently, we demonstrated that the cell-surface level of endomucin (EMCN), a heavily O-glycosylated single-transmembrane sialomucin, interferes with the interactions between inflammatory cells and ECs. We have also shown that, in response to an inflammatory stimulus, EMCN is cleared from the cell surface by an unknown mechanism. In this study, using adenovirus-mediated overexpression of a tagged EMCN in human umbilical vein ECs, we found that treatment with tumor necrosis factor α (TNF-α) or the strong oxidant pervanadate leads to loss of cell-surface EMCN and increases the levels of the C-terminal fragment of EMCN 3- to 4-fold. Furthermore, treatment with the broad-spectrum matrix metalloproteinase inhibitor batimastat (BB94) or inhibition of ADAM metallopeptidase domain 10 (ADAM10) and ADAM17 with two small-molecule inhibitors, GW280264X and GI254023X, or with siRNA significantly reduced basal and TNFα-induced cell-surface EMCN cleavage. Release of the C-terminal fragment of EMCN by TNF-α treatment was blocked by chemical inhibition of ADAM10 alone or in combination with ADAM17. These results indicate that cell-surface EMCN undergoes constitutive cleavage and that TNF-α treatment dramatically increases this cleavage, which is mediated predominantly by ADAM10 and ADAM17. As endothelial cell-surface EMCN attenuates leukocyte–EC interactions during inflammation, we propose that EMCN is a potential therapeutic target to manage vascular inflammation.

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.

The event discussion, which touched on the intersection of race and immigration, focused on the demographics of Black immigrants (both African and Caribbean) in the United States and their children, their educational success, and the implications of the recently released volume’s findings for research and public policy.

Book release event for MPI's volume on the Children of Black Immigrants, covering topics of education, health, and demographics, with U.S. Department of Health and Human Services Deputy Assistant Secretary for Human Services Policy Ajay Chaudry; Gerald D. Jaynes, Yale University Departments of Economics and African-American Studies; chapter authors Dylan Patricia Conger and Kevin Thomas; and volume editors MPI's Randy Capps and Michael Fix.

This interdisciplinary volume examines the health, well-being, school readiness, and academic achievement of children in Black immigrant families (most with parents from Africa and the Caribbean)—a population that has had little academic attention even as it represents an increasing share of the U.S. Black child population.

New findings challenge our understanding of how the brain matures

Faces are important to us. From the moment we are are born, we prefer to look at faces than at other, inanimate objects, and, being social animals, we encounter faces every day of our lives. The face is the first thing we look to when identifying other people; faces also convey emotions, informing us of peoples’ mood, and from them we can usually determine a person’s sex and, sometimes, roughly how old they are. Eye movements can also reveal to us something about another person’s intentions.

Related: How your eyes betray your thoughts

Related: Live imaging of synapse density in the human brain

(May 4, 2020) On April 29, 2020, the Swedish National Prosecutor announced that it is investigating a workplace environment crime (arbetsmiljöbrott) after a nurse working at Karolinska University Hospital in Stockholm died of COVID-19. The investigation comes following a report by the local safety representative (skyddsombud), who reportedly claimed that the hospital lacked the appropriate […]

Why does Bollywood use the offensive practice of brownface in movies?  CNN

On Mother’s Day, be inspired by these mother-daughter duos who are going places  YourStory

In this second update from the Serbia/Croatia border, OM leader Volker Sachse describes moments of God’s peace that transforms people in a dire situation.

Sometimes it's not about handing out blankets, meals or having conversations, noticed OM worker Elizabeth when volunteering in the refugee ministry in Serbia.

Mahmood, a refugee from Sudan, travelled the 'West Balkan' migrant route. Months later, settled in The Netherlands, he recalls worship in OM's tent in Serbia.

Michael (Kenya) participates in a short-term mission trip to Romania and gives an account of God's transforming power at work amongst the Roma people.

Hope for Zurich connects with the community at Träff International, their outreach to the local immigrant population.

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

Kochi, India :: Jeannette Zandbergen (Netherlands) is surprised to see an old friend in a photograph.

The Chaotic Scots Traveller Kay Gillespie delivers her Top 10 places She's dreaming about in Scotland

By Deborah Anderson

Seeing that there were few affordable activities for teens in Dobrinja, Bosnia, the OM team launches The House, a comfortable, safe place for young people.

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.

God used a dangerous situation to change the life of a Salvadorian woman.