dia FMCG Production and Quality recruitment in India. By jobs.monsterindia.com Published On :: 2020-03-05 16:11:18 Company: S R IT ServicesExperience: 0 to 5location: Indore, NashikRef: 24731858Summary: FMCG Production and Quality Requirements and also Food Beverages. Full Article
dia Canada Head Sales-Ludhiana (Counselor Head, Sales Manager,Canadian Education/Immigration VISA) By jobs.monsterindia.com Published On :: 2020-02-27 23:07:29 Company: P & I Management ConsultantsExperience: 6 to 9location: India, LudhianaRef: 24657059Summary: Job Description: Job Description Graduate with over 6 years experience in Sales and Counseling for Immigration to Canada and arranging Study Visa for Canada. Must be expert in Agent-Networking for Immigration Services, .... Full Article
dia Immediate Hiring For Python Developer By jobs.monsterindia.com Published On :: 2019-12-08 14:21:04 Company: SP Staffing Services Private LimitedQualification: OtherExperience: 1 to 5Salary: 3.50 to 6.10location: ChennaiRef: 24374534Summary: Immediate Hiring For Python Developer Full Article
dia Richard Gregory, comedian and activist, 1932-2017 By www.ft.com Published On :: Fri, 25 Aug 2017 15:39:26 GMT A trailblazing satirist who battled racial injustice in America Full Article
dia Trump vs Biden: will healthcare be the decider? | DC lockdown diary By www.ft.com Published On :: Sun, 10 May 2020 14:16:14 GMT Healthcare for the unemployed set to become key election issue Full Article
dia Athlete's Foot: Causes, Symptoms, Diagnosis, Treatment And Prevention By www.boldsky.com Published On :: Wed, 06 May 2020 11:33:10 +0530 Athlete's foot (AF), also known as tinea pedis is a fungal infection of the foot, mostly found between the toes. It is named so as the infection is common in athletes and swimmers. The AF can spread to hands or other Full Article
dia Coronavirus wrap May 9 | First repatriation flight from London takes off for Mumbai with 326 Indians By www.moneycontrol.com Published On :: Sat, 09 May 2020 20:51:51 +0530 Here are the key developments related to Coronavirus pandemic on May 9. Full Article
dia Navy's INS Jalashwa brings back 698 Indians from Maldives as part of Samudra Setu mission By www.dnaindia.com Published On :: Sun, 10 May 2020 09:59:00 GMT As part of the Mission Samudra Setu, INS Jalashwa reached Maldives on May 7 to evacuate Indian nationals. Full Article India
dia Martinů's subliminal states: a study of the composer's writings and reception, with a translation of his American diaries / Thomas D. Svatos By library.mit.edu Published On :: Sun, 10 May 2020 07:43:52 EDT Lewis Library - ML410.M382 A3 2018 Full Article
dia Nadia Boulanger and the Stravinskys: a selected correspondence / edited by Kimberly A. Francis By library.mit.edu Published On :: Sun, 10 May 2020 07:43:52 EDT Lewis Library - ML423.B52 A4 2018 Full Article
dia Lockdown: Air India flight brings home 239 Indians from UK By www.thehindubusinessline.com Published On :: Sun, 10 May 2020 13:51:04 +0530 An Air India flight landed here from London at 1.30 am on Sunday carrying 239 Indians from the UK who were stranded there due to suspension of commer Full Article Logistics
dia India needs ‘whole-of-govt approach’ to confront strategic uncertainties: Army Chief By www.thehindubusinessline.com Published On :: Sun, 10 May 2020 17:43:23 +0530 The time has come for India to adopt a “whole-of-government approach” in decisively confronting the “strategic uncertainties” looming on its horizon a Full Article Policy
dia India’s coal production to clock record 700 million tonnes in FY21: Coal Secretary By www.thehindubusinessline.com Published On :: Sun, 10 May 2020 18:04:52 +0530 Coal Secretary Anil Jain said FY20 coal production was lower than the target of 660 million tonnes because of flooding of a key coal mine. Full Article Economy
dia Few HDB Financial Services employees take to social media after being laid off By www.thehindubusinessline.com Published On :: Sun, 10 May 2020 22:00:08 +0530 HDFC Bank says “minuscule” number of employees told to leave as part of annual appraisal process Full Article Money & Banking
dia Pause in global college admissions is a chance for India to reverse its student exodus By www.thehindubusinessline.com Published On :: Sun, 10 May 2020 19:31:35 +0530 Convincing migrating students to stay with domestic options post-Covid will require sweeping reforms in the education system Full Article Editorial
dia From May 12, Indian Railways to resume select passenger train services By www.thehindubusinessline.com Published On :: Sun, 10 May 2020 21:39:37 +0530 Railways will start online reservation for special trains with effect from 4 pm on May 11 Full Article Logistics
dia The Covid challenge to Indian school education: Reform or perish By www.thehindubusinessline.com Published On :: Sun, 10 May 2020 22:14:46 +0530 Reluctant schools and teachers have been forced to adapt to e-learning Full Article Education
dia Air India ready to fly Indian seafarers overseas to join ships By www.thehindubusinessline.com Published On :: Sun, 10 May 2020 22:11:49 +0530 But, logistic issues could torpedo the plan Full Article Logistics
dia India must now help its people back to work By www.ft.com Published On :: Sun, 10 May 2020 17:07:17 GMT Fiscal constraints should be put aside to support the country through Covid-19 Full Article
dia Watch: David Warner lip-syncs Mahesh Babu's famous 'Pokiri' dialogue on TikTok By www.dnaindia.com Published On :: Sun, 10 May 2020 12:26:00 GMT Before this, David and his wife Candice were seen grooving to recent Telugu hit track Butta Bomma from Allu Arjun starrer Ala Vaikuntapuramlo. Full Article Entertainment
dia India-China face-off in north Sikkim, troops from both sides reportedly injured By www.dnaindia.com Published On :: Sun, 10 May 2020 13:44:00 GMT News reports suggest that a total of 150 soldiers were involved in the face-off that allegedly took place a few days back. Full Article India
dia Mission Sagar: India's helping hand across Indian Ocean during COVID-19 crisis By www.dnaindia.com Published On :: Sun, 10 May 2020 14:16:00 GMT This deployment is in line with India's role as the first responder in the region. Full Article India
dia South Korea takes first cautious steps into a post-Covid world - The Guardian By news.google.com Published On :: Sun, 10 May 2020 05:45:39 GMT South Korea takes first cautious steps into a post-Covid world The GuardianS. Korea warned of COVID-10 second wave NEWS.com.auSouth Korea reverses on reopenings amid nightclub outbreak The AgeS.Korea leader says no panic as cases rise SBS NewsCoronavirus: How South Korea 'crushed' the curve BBC NewsView Full coverage on Google News Full Article
dia NSW warns ‘complacency biggest threat’ as most states move to ease Covid-19 restrictions - The Guardian By news.google.com Published On :: Sun, 10 May 2020 04:45:46 GMT NSW warns ‘complacency biggest threat’ as most states move to ease Covid-19 restrictions The GuardianNSW coronavirus restrictions to lift from Friday, but will not follow all National Cabinet measures ABC NewsCoronavirus Australia: NSW Premier issues firm warning to NSW residents Jimmys PostNSW to ease lockdown restrictions from Friday Sydney Morning HeraldNSW Premier Gladys Berejiklian says relaxation of restrictions doesn't mean coronavirus is less deadly ABC NewsView Full coverage on Google News Full Article
dia Ten arrested and police officer injured at protest against Victoria’s Covid-19 lockdown laws - The Guardian By news.google.com Published On :: Sun, 10 May 2020 08:00:46 GMT Ten arrested and police officer injured at protest against Victoria’s Covid-19 lockdown laws The GuardianHundreds of anti-vaxxers clash with police during protest in Melbourne's CBD Daily MailCoronavirus: Anti-lockdown protesters clash with police in Melbourne NEWS.com.auTen arrested, police officer injured in anti-lockdown protest The AgeCoronavirus Australia updates: anti-lockdown protest in Melbourne as NSW and WA set to ease Covid-19 restrictions – as it happened The GuardianView Full coverage on Google News Full Article
dia NoirMale: Dillon Diaz By feeds.queerclick.com Published On :: Sun, 10 May 2020 04:12:26 +0000 Dr. Dillon Diaz is accepting new patients, he specializes in deep cavity research. See more at NoirMale. The post NoirMale: Dillon Diaz appeared first on QueerClick. Full Article Porn Site Updates Dillon Diaz NoirMale
dia EPA and Indiana Announce Indianapolis, Muncie, Lake and Porter Counties Now Meet Federal Air Quality Standards By www.epa.gov Published On :: Tue, 28 Apr 2020 00:00:00 -0400 WASHINGTON (April 28, 2020) — Today, the U.S. Environmental Protection Agency (EPA) and State of Indiana announced that recent air monitoring data show the city of Indianapolis, and the areas of Muncie, Lake and Porter counties are meeting federal air quality standards. Full Article
dia 2018's best Indiana college football matchups By rssfeeds.indystar.com Published On :: Wed, 11 Jul 2018 14:52:48 +0000 Games involving Notre Dame, Purdue and Indiana could have a lot at stake this season. Full Article
dia IndyStar sports app: The best coverage of your favorite Indiana teams, all in one place By rssfeeds.indystar.com Published On :: Fri, 05 Jan 2018 20:32:42 +0000 Now you can read all of IndyStar's sports content in one place with our free INSports app. Full Article
dia From Notre Dame to the Monon Bell: Ranking Indiana's top 50 college football games in 2018 By rssfeeds.indystar.com Published On :: Wed, 11 Jul 2018 18:42:23 +0000 From Notre Dame to the Monon Bell. We rank Indiana's top 50 college football games in 2018. Full Article
dia Police investigate death on Indianapolis' near northeast side By rssfeeds.indystar.com Published On :: Sat, 09 May 2020 20:22:06 +0000 Indianapolis Metropolitan Police Department are on the scene in the area of East 32nd Street and Baltimore Avenue. Full Article
dia Police investigate death on Indianapolis' near northeast side By rssfeeds.indystar.com Published On :: Sat, 09 May 2020 20:22:06 +0000 Indianapolis Metropolitan Police Department are on the scene in the area of East 32nd Street and Baltimore Avenue. Full Article
dia NVidia, AMD Battle To Buy Out TSMC's Capacity By rss.slashdot.org Published On :: 2020-05-10T01:34:00+00:00 Long-time Slashdot reader UnknowingFool writes: As NVidia and AMD battle it out with their GPUs in consumer gaming, behind the scenes both manufacturers were competing against each for manufacturing capacity with TSMC's lines. It appears that early on in the 7nm line, NVidia lost out as it is rumored their strategy was to use Samsung more only to go back to TSMC when that failed By then TSMC had sold out their capacity to AMD. For their next generation GPUs it appears both NVidia is securing both 5nm early while grabbing as much 7nm as possible. Read more of this story at Slashdot. Full Article
dia Earthquake of magnitude 3.5 hits Delhi-NCR - Times of India By news.google.com Published On :: Sun, 10 May 2020 09:40:38 GMT Earthquake of magnitude 3.5 hits Delhi-NCR Times of IndiaMagnitude 3.4 Earthquake Strikes Delhi, Epicentre Near UP Border News183.5 Magnitude Earthquake Hits Delhi-NCR, no Casualty Reported India.comBreaking news live : Eathquake tremors felt in Delhi, adjoining areas Times of IndiaEarthquake in Delhi: Tremors felt in national capital region The Financial ExpressView Full coverage on Google News Full Article
dia Apple India Website Puts Siri in Silent Mode By labnol.tumblr.com Published On :: Sat, 26 Nov 2011 15:33:09 +0530 Apple India Website Puts Siri in Silent Mode Full Article
dia Coronavirus doctor's diary: The strange case of the choir that coughed in January By www.bbc.co.uk Published On :: Sun, 10 May 2020 00:12:16 GMT Dr John Wright is intrigued by some singers who became ill long before the UK's first known Covid-19 case. Full Article
dia Sorry Indianapolis, You're No Longer the Sole Location Offering TSA PreCheck Enrollment Background Checks By feedproxy.google.com Published On :: Mon, 16 Dec 2013 15:07:00 EST Filed under: North America, United States Getty Two weeks ago, the Transportation Security Administration announced that it would began allowing travelers to apply for its PreCheck program, "an expedited screening process" through airport security. Curiously though, the only airport in the country where travelers could complete the program's required background interview was Indianapolis International Airport. That changed today when TSA opened three enrollment centers in the Washington, DC area. Interestingly, none of them are at DC-area airports. Nor are any of them in DC itself.Continue reading Sorry Indianapolis, You're No Longer the Sole Location Offering TSA PreCheck Enrollment Background ChecksSorry Indianapolis, You're No Longer the Sole Location Offering TSA PreCheck Enrollment Background Checks originally appeared on Gadling on Mon, 16 Dec 2013 15:07:00 EST. Please see our terms for use of feeds.Permalink | Email this | Comments Full Article Alexandria PreCheck Transportation Security Administration TSA Virginia Washington DC
dia 'Happy to be out': Canadian cruise ship crew members return home after months at sea By www.ctvnews.ca Published On :: Sat, 9 May 2020 21:22:50 -0400 Canadians working aboard two cruise ships who weren't allowed to come to shore because of concerns about COVID-19 are finally able to return home. Full Article
dia US and India: The Best is (Still) Yet to Come By feedproxy.google.com Published On :: Tue, 27 Jan 2015 10:18:50 +0000 27 January 2015 Xenia Wickett @xeniawickett LinkedIn Former Head, US and the Americas Programme; Former Dean, The Queen Elizabeth II Academy for Leadership in International Affairs The US-India relationship is full of potential, but until there is a sustained commitment from the countries’ leaders, it will remain largely unrealized. 20150127ObamaModi.jpg Indian Prime Minister Narendra Modi and US President Barack Obama leave after speaking during the India-US Business Summit in New Delhi on 26 January 2015. Photo by Getty Images. On 26 January, President Barack Obama joined Prime Minister Narendra Modi as his guest at India’s Republic Day, in a reflection of the huge potential in the US-India relationship. The trip makes Obama the first US president to visit India twice while in office, and comes on the heels of Modi’s visit to Washington last autumn. Nevertheless, the heavily touted ‘transformation’ in bilateral affairs that these summits are supposed to herald is unlikely to materialize soon. Continued, active and deliberate effort by the two leaders could allow the relationship to jump forward, but given competing priorities, this moment seems destined to pass without the major advances many believe are possible.Since the 2005 breakthrough nuclear deal which brought India into the non-proliferation tent, the opportunities in the bilateral relationship have been loudly extolled. Notably, the countries lack historical closeness − during the Cold War, India led the Non-Aligned Movement but leaned towards the Soviet Union. This means that there is ample opportunity to progress in a number of key areas – but also is indicative of the challenges.DemocracyIt is often said that India is the largest democracy and the United States the oldest. President George W. Bush saw India as a valuable partner in promoting democracy around the region and the world. India’s loud, raucous political system should be a good example of a vibrant democracy. However, India, like China, holds strongly to the primacy of sovereignty and as such has no wish to lead others to build new political systems or to impose them.Economics and tradeIndia has a middle class that is, by some counts, larger than the entire US population. However, India’s regulatory system is complex, and its legal architecture slow and unpredictable. After recent Indian decisions such as the 2012 case where retroactive taxes were imposed on Vodafone, American businesses have been extremely wary. Tensions at a governmental level were also raised in America after India collapsed the WTO negotiations last July.SecurityMajor strides have been taken in military cooperation, and there is space for more. During Obama’s visit, the two leaders revitalized their Defence Framework, building on a 2005 agreement and subsequent progress led by then-US deputy secretary of defense Ash Carter. Carter’s likely confirmation as secretary of defense in the coming weeks is probably the brightest spot for the future bilateral agenda. But Indian acquisition processes do not align well with their American equivalents. And the US is resistant to providing blueprints to technology, which the Indians want, preferring to build at home and sell the equipment on. These misalignments make progress in this area difficult.GeopoliticsIndia wants to be considered a regional and global power, and America would dearly like to have India onside, particularly in light of China’s occasional muscle flexing. However, as illustrated by its uncritical stance towards Russia’s annexation of Crimea and its abstention from the 2011 UN Security Council resolution authorizing military action in Libya, India’s view on sovereignty and its historical non-aligned positioning mean that it too often fails to back up the US on divisive issues.EnvironmentThe environmental debates between India (as a representative of the developing world) and the US (representing the developed) have often been acrimonious, as the two sides take opposing views on where the principal responsibility lies in ensuring growth while limiting the environmental fallout. There are however opportunities in this arena to advance together through technology cooperation. India is the third-largest emitter of greenhouse gases (behind China and the US) and has significant and growing energy demands as it works to bring its people out of poverty. If the US and India could find a compromise similar to the recent agreement between the US and China, the impact could be significant both in environmental terms and in the demonstration effect to others.Unrealized potentialMost of these issues are central to President Obama’s legacy and integral to Modi’s goals of restoring growth to India and putting it at the centre of global geopolitics. They should dovetail well with both leaders’ agendas. But in each case, the challenges, including the institutional bureaucracies, are preventing real breakthroughs.If this bilateral relationship is to be transformed, Obama and Modi need to not just push their systems, but exert sustained pressure on them to overcome the long-standing obstacles. Unfortunately, given other agendas and historical legacies of distrust, such ongoing attention is unlikely. More likely, the relationship will continue to move ahead, but the huge potential will for now remain unrealized.To comment on this article, please contact Chatham House Feedback Full Article
dia India Under Modi: A Superpower in the Making? By feedproxy.google.com Published On :: Mon, 23 May 2016 10:15:01 +0000 Members Event 30 June 2016 - 1:00pm to 2:00pm Chatham House London, UK Event participants Dr Mukulika Banerjee, Director, South Asia Centre, London School of EconomicsNandan Nilekani, Co-founder and Chairman, EkStep; Chairman, Unique Identification Authority of India (UIAI) (2009-14)Dr Gareth Price, Senior Research Fellow, Asia Programme, Chatham HouseMihir Swarup Sharma, India Columnist, Bloomberg View; Senior Fellow, Observer Research Foundation, New DelhiChair: James Crabtree, Contributing Editor, Financial Times; Senior Visiting Fellow, Lee Kuan Yew School of Public Policy On the surface, the Indian economy is performing well, and the popularity of Narendra Modi, the prime minister elected on the promise of liberalizing reform two years ago, is holding up. Christine Lagarde, the managing director of the International Monetary Fund (IMF), has referred to India as a ‘bright spot’ in the slowing global economy. According to them, growth equalled China’s last year at 7.3% and has now taken the lead as the world’s fastest growing economy. Yet some joke that India’s prospects look brighter the farther away you are.The panel will reflect on Modi’s two years in power and discuss what they think the government got wrong and what they got right. They will question whether India’s resurgence can be sustained into the future, and discuss what this actually means for the prospects of India’s 1.3 billion people, as well as the balance of power in Asia and beyond.This event is organized in association with the Lee Kuan Yew School of Public Policy at the National University of Singapore. Members Events Team Email Full Article
dia Review article: Understanding change and continuity in India’s foreign policy By feedproxy.google.com Published On :: Fri, 06 Jan 2017 10:22:18 +0000 6 January 2017 , Volume 93, Number 1 Aseema Sinha The field of Indian foreign policy is rich and wide ranging, offering new empirical material across a broad array of topics and relationships. This article reviews three recent books on the subject, with an eye towards evaluating change amid continuity in the pursuit of Indian foreign policy. This scholarship calls out for a new paradigm to understand India’s changing position and actions at global, regional and domestic levels. I argue that Indian foreign policy can and should be seen through the prism of an open border, interdependence framework, wherein both the domestic and global levels are analysed in a linked manner. While the literature surveyed here does not yet offer a new paradigm, some common findings suggest the need for new approaches. We also need to find and use new sources of data and seek ways to measure institutional effects in foreign policy. The task of measurement and theoretical modelling is made more challenging by the need to theorize the linkages across levels and to measure foreign policy variables in different countries simultaneously. Related documents INTA93_1_11_Sinha.pdfpdf | 80.92 KB Full Article
dia South Dakota Governor demands Sioux tribes 'immediately' remove COVID-19 checkpoints because they interfere with traffic By news.yahoo.com Published On :: Sat, 09 May 2020 17:44:40 -0400 South Dakota Governor Kristi Noem sent letters to two Sioux tribes demanding they remove COVID-19 checkpoints because they interfere with traffic. Full Article
dia Nepal protests new Indian road through disputed territory By news.yahoo.com Published On :: Sat, 09 May 2020 10:48:11 -0400 Nepal protested India's inauguration of a new road to China that passes through territory claimed by Kathmandu on Saturday, with police arresting dozens demonstrating close to India's embassy. Indian defence minister Rajnath Singh on Friday inaugurated via video link the 80-kilometre (50 miles) long road from Ghatiabagarh in northern Uttarakhand state to the Lipu Lekh pass high in the Himalaya. The pass is claimed by Nepal based on an 1816 treaty that defines its western border with India. Full Article
dia Elon Musk says Tesla will 'immediately' leave California after coronavirus shutdowns forced the company to close its main car factory By news.yahoo.com Published On :: Sat, 09 May 2020 13:34:00 -0400 In a tweet Saturday morning, Tesla's chief executive said it would file a lawsuit against county officials over not being able to run its factory. Full Article
dia NF-{kappa}B mediates lipopolysaccharide-induced alternative pre-mRNA splicing of MyD88 in mouse macrophages [Signal Transduction] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Although a robust inflammatory response is needed to combat infection, this response must ultimately be terminated to prevent chronic inflammation. One mechanism that terminates inflammatory signaling is the production of alternative mRNA splice forms in the Toll-like receptor (TLR) signaling pathway. Whereas most genes in the TLR pathway encode positive mediators of inflammatory signaling, several, including that encoding the MyD88 signaling adaptor, also produce alternative spliced mRNA isoforms that encode dominant-negative inhibitors of the response. Production of these negatively acting alternatively spliced isoforms is induced by stimulation with the TLR4 agonist lipopolysaccharide (LPS); thus, this alternative pre-mRNA splicing represents a negative feedback loop that terminates TLR signaling and prevents chronic inflammation. In the current study, we investigated the mechanisms regulating the LPS-induced alternative pre-mRNA splicing of the MyD88 transcript in murine macrophages. We found that 1) the induction of the alternatively spliced MyD88 form is due to alternative pre-mRNA splicing and not caused by another RNA regulatory mechanism, 2) MyD88 splicing is regulated by both the MyD88- and TRIF-dependent arms of the TLR signaling pathway, 3) MyD88 splicing is regulated by the NF-κB transcription factor, and 4) NF-κB likely regulates MyD88 alternative pre-mRNA splicing per se rather than regulating splicing indirectly by altering MyD88 transcription. We conclude that alternative splicing of MyD88 may provide a sensitive mechanism that ensures robust termination of inflammation for tissue repair and restoration of normal tissue homeostasis once an infection is controlled. Full Article
dia Inter-{alpha}-inhibitor heavy chain-1 has an integrin-like 3D structure mediating immune regulatory activities and matrix stabilization during ovulation [Glycobiology and Extracellular Matrices] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 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. Full Article
dia Glycation-mediated inter-protein cross-linking is promoted by chaperone-client complexes of {alpha}-crystallin: Implications for lens aging and presbyopia [Glycobiology and Extracellular Matrices] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 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. Full Article
dia Processivity of dextransucrases synthesizing very-high-molar-mass dextran is mediated by sugar-binding pockets in domain V [Glycobiology and Extracellular Matrices] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 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. Full Article
dia ADAM10 and ADAM17 proteases mediate proinflammatory cytokine-induced and constitutive cleavage of endomucin from the endothelial surface [Membrane Biology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 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. Full Article
dia Re: Prognosis of unrecognised myocardial infarction determined by electrocardiography or cardiac magnetic resonance imaging: systematic review and meta-analysis By feeds.bmj.com Published On :: Saturday, May 9, 2020 - 18:01 Full Article