Research Event

Event participants

Charlie Parton, Counsellor, Political Section, Beijing Delegation, European External Action Service
Chair: Roderic Wye, Assciate Fellow, Asia Programme, Chatham House

30 September 2015

GAZIANTEP, Turkey—After five years fighting to preserve Bashar al-Assad’s regime in Syria, Russia now appears inclined to dispose of its infamous client. Assad’s persistent brutality and corruption, and his inability to establish even the semblance of a functioning state, has grown to be a burden Moscow would prefer not to bear.And then there’s the problem of Iran. Assad, members of his family, and his Alawite clansmen enjoy close, perhaps unbreakable, bonds to the regime in Tehran and to Iranian-backed militias in Syria. All of which undermines Moscow’s primary mission there: to rehabilitate the Assad regime as a symbol of stability capable of attracting hundreds of billions of dollars of foreign investment for reconstruction, which Russian firms would then be poised to receive. As long as Assad’s relatives continue to function as a mafia and give free rein to Iranian troops using Syria as base of operations to threaten Israel and plan attacks against U.S. troops in Iraq, those countries likely to foot the bill for Syrian reconstruction—the nations of Europe and the Gulf—are unlikely to come up with the cash. Amid Escalating Syrian Carnage, Turkey Shoots Down Assad’s PlanesThis has not gone unnoticed by the United States.“Assad has done nothing to help the Russians sell this regime,”James Jeffrey, the U.S. special envoy for the Coalition to Defeat ISIS, told reporters in a State Department briefing on Thursday. “You find Assad has nothing but thugs around him, and they don't sell well either in the Arab world or in Europe. We have heard repeatedly from Russians we take as credible that they understand how bad Assad is.” The Syrian president’s “refusal to make any compromises” in order to secure diplomatic recognition and acceptance for his regime has jeopardized “hundreds of billions of dollars in reconstruction assistance” for Syria, according to Jeffrey. Yet the Trump administration is unlikely to exploit this growing rift. “Getting Russia out of Syria,” Jeffrey said, “has never been our goal. Russia has been there for 30 years. It has a long-term relationship with Syria. We don’t think it has been healthy for the region. We don’t think it really is even healthy for Russia. But that’s not our policy.”  MEDIA FRENZYJeffrey’s statements come just one week after Russian state media unleashed a slew of reports and editorials targeting Assad, portraying the beleaguered president as hopelessly corrupt and unfit to govern, and suggesting the time had come to replace him with a new leader.The first batch of articles was published by the Russia’s Federal News Agency (FNA), an outlet owned by Yevgeny Prigozhin, a Russian oligarch and chairman of several companies implicated in the 2016 U.S. elections scandal. Appearing over the course of a mere three hours on April 17, they would shake Syria to its core. The first of the three articles in question highlighted a corruption scheme carried out by the regime in summer 2019 in which the Syrian prime minister purportedly lied to citizens about oil and gas scarcities in order to justify the occurrence of long power outages while selling Syrian electricity to businessmen in Lebanon. The second piece cited an opinion poll claiming only 32 percent of Syrians would vote for Assad in the country’s upcoming 2021 presidential election. The third and final article, entitled, “Corruption is Worse than Terrorism,” chastized President Assad for personally failing to combat corruption, prevalent at all levels of the state.  That these were published by Prigozhin’s news agency was the kind of signal it would be hard for Assad to miss. Prigozhin, who first built his fortune as a caterer, is sometimes known as “Putin’s chef.” But of particular relevance to Syria is his role as chairman of the Wagner Group, whose mercenaries have fought alongside Assad regime forces since October 2015 and helped the latter take back control of key revenue generating infrastructure such as the al-Sha’ir gas field in Homs province.Deputy Assistant Secretary Christopher Robin told the same State Department briefing Thursday, “Wagner is often misleadingly referred to as a Russian private military company, but in fact it’s an instrument of the Russian government which the Kremlin uses as a low-cost and low-risk instrument to advance its goals.”The article on corruption would also point out, suggestively, that the Assads are not the only powerful family in Syria, “there are also the Makhloufs.”Rami Makhlouf, who is in fact Bashar al-Assad’s first cousin, is Syria’s wealthiest man, and also, it would seem, Russia’s man. Certainly he has strong ties to the Kremlin and for years has been one of the most vocal critics of Iran’s presence in Syria. In July 2018, the al-Watan newspaper, one Syria’s most prominent pro-regime mouthpieces and owned by Rami Makhlouf since 2006, published a then unprecedented public rebuke to Iran, accusing it of sponsoring Islamist fanaticism throughout the Middle East alongside Turkey and Qatar, the main backers of Syria’s opposition. (Rami Makhlouf’s father Muhammad and brother Hafiz meanwhile are alleged by some to be living in Russia.) The April 17 articles published by Prigozhin’s FNA preceded the release of a wave of other articles and items in the media over the next 12 days that would further drive home the point that Moscow was considering options other than Assad to rule Syria. TASS, Russia’s largest state-run news agency, wrote in one editorial that, “Russia suspects that Assad is not only unable to lead the country anymore, but also that the head of the Syrian regime is dragging Moscow towards the Afghani scenario.” This is like evoking the Vietnam War for an American audience, a reference to the Kremlin’s botched campaign through the 1980s that helped bankrupt the Soviet Union and finally break it apart.Amid this coverage, TASS would also take swipes at Iran, claiming that the Islamic Republic has “no interest in achieving stability in the region, because it considers it a battlefield with Washington”.On April 30, the Russian International Affairs Council (RIAC), a think tank established by Moscow’s Ministry of Foreign Affairs, released a scathing report saying Russia was in talks with other parties to the Syrian conflict to draw up plans for a political resolution that did not include Bashar al-Assad as president. The report highlighted purported Russian efforts to compel the Syrian regime to commit to ceasefires with both American-backed and Kurdish-led Syrian Democratic Forces (SDF), and the Turkish-backed Free Syrian Army (FSA) opposition, while beginning steps to form a new unity government that would include representatives from both. That day, Rami Makhlouf, whose assets were frozen five months earlier as part of a tax dispute, uploaded a video onto his personal Facebook page accusing the Assad regime of corruption. In a state known for carrying out the full-scale slaughter of those who test its authority, Makhlouf’s videos, coming on the heels of the unprecedented Russian attacks in the media, sent shockwaves throughout the country.  THE ROYAL FAMILYWhile the Makhlouf clan clearly has thrown its lot in with Russia, key members of Bashar al-Assad’s immediate family and others with ties to Qardaha in Syria’s largely Alawite Latakia province, are among the most prominent Iranian-backed militia leaders in Syria. It’s an alliance that traces back to his father Hafez al-Assad, who was born in Qardaha, and who forged ties with the Iranian revolution almost from its beginning more than 40 years ago. The Iranians responded by offering religious legitimacy to the Alawite sect, which is regarded as heretical by Sunnis and indeed by many Shi’a.These Qardaha militia leaders have regularly engaged in armed clashes against Russian backed units. They are among the most egregious violators and abusers of power, overseeing wide networks of corruption similar to those lamented in the Russian media. And foremost among them is Bashar’s younger brother, Maher al-Assad. Since April 2018, Maher al-Assad has commanded the Syrian Army’s 4th Armored Division, one of country’s oldest, best equipped and overwhelmingly Alawite brigades. After the 2011 outbreak of the Syrian revolution, when the loyalty of much of the army was in doubt, it became a refuge for numerous Alawite-Shi’a dominated pro-regime militias.Currently, the 4th Armored Division’s members control many smuggling operations throughout the country, in cities from Albu Kamel on Syria’s eastern border with Iraq to Latakia on the Syrian coast, where the port was leased to Iran on October 1 last year. It has since become one of the biggest export hubs for drugs headed to markets in Europe, the Middle East and North Africa. Examples abound: On July 5, 2019, Greek coast guard and drug enforcement officials announced the biggest drug bust in history, seizing 5.25 tons (33 million pills) of Captagon amphetamines worth $660m hidden in shipping containers loaded at the Latakia port in Syria. That followed a long string of such seizures made by Greek authorities. More recently, in late April, customs officials in both Saudi Arabia and Egypt also announced the seizure of similar quantities of drugs in containers traced back to Latakia. Local reports have accused a range of actors including Maher al-Assad’s 4th Division, Hizbollah, Rami Makhlouf, and others of profiting from the massive drug exports emanating from the port. In January 2019 the 4th Armored Division launched attacks on the Russian-backed Tiger Forces unit in an attempt to wrest control of smuggling routes between regime- and opposition-held territory in Idlib province. The clashes led to the death of 70 fighters. These and other skirmishes prompted Russia to back a major campaign to arrest 4th Division and other Iranian-backed units throughout the country beginning in April 2019, which succeeded in rounding up numerous mid-ranking Iranian-backed officers. Among those targeted in the campaign was Bashar Talal al-Assad, a cousin to the president (similar name, different people) who was wanted on drug and weapons trafficking charges. Unlike others who were detained in the roundup, Bashar Talal al-Assad and his ‘Areen Brigade managed to fight off Russian-backed forces that sought to arrest him in Qardaha. He then pledged to attack Russia’s Hmeimim military base, located 17 miles east of Latakia city, in the event the regime sought to arrest him again.For Russia, the threat of such attacks on its military infrastructure is a real concern. The Hmeimim base—from which Moscow has directed its entire military campaign in Syria—had already been subject to a series of attacks from January to October 2018 by other Iranian-backed militias in the area. The threat posed by both Iran’s acquisition of the Latakia port and its support for local Assad family proxies in Syria’s coastal region is exacerbated by the fact that Tehran has also begun making progress toward completing construction of its Shalamcha railroad, which, via stops in Basra, Baghdad, Albu Kamel and Damascus, will give Tehran direct access to the Syrian and Lebanese coasts. If Iran succeeds in integrating the Latakia port with the Shalamcha rail line, this will cut off Hmeimim from Russian forces in central and southern Syria and enable Tehran to quickly deliver weapons to proxy forces in Latakia that are already engaged in clashes against Russian-backed groups. WORLDWIDE CONSENSUSMoscow’s inability to control Iranian backed Syrian militiamen engaged in widespread crime, corruption, and assaults on Russian forces has infuriated the Kremlin. But Russia is not the only major player on the ground with scores to settle against Iran, and the Russian military leadership in Syria has ignored if not largely encouraged Israeli strikes on Iranian troops throughout the country.It may not be coincidental that the Israeli attacks have increased in pace and scope since April, following the flurry of Russian media articles attacking Assad and his regime. “We have moved from blocking Iran’s entrenchment in Syria to forcing it out of there, and we will not stop,” Israel’s new defense minister, Naftali Bennett, declared on April 28. Without Russia, Iran has found itself the odd man out in Syria, the single party still seeking to push for war at a time when most other international players have been struck with fatigue and simply seek to put Syria’s pieces back together. President Recep Tayyip Erdoğan of Turkey, the last patron of Syria’s battered FSA opposition, has himself made peace with Moscow, effectively agreeing last March to cede control of wide swaths of rebel held territory after a particularly bloody Russian led campaign against the last FSA holdout in Idlib province that ended in victory for regime forces. Ironically, Erdoğan’s long-held desire to overthrow Syria’s president may still come to fruition, albeit not as he expected, as Assad’s ouster may come at the hands of Russia itself, and not the revolution. Read more at The Daily Beast.Get our top stories in your inbox every day. Sign up now!Daily Beast Membership: Beast Inside goes deeper on the stories that matter to you. Learn more.

Some Buckeyes are not comfortable being told by a "woman in power" to quarantine, one expert said.

"I think it's always important to think about suicide as individual vulnerabilities and context," Eric Caine said.

China's National Health Commission reported 14 new confirmed coronavirus cases on May 9, the highest number since April 28, including the first for more than a month in the city of Wuhan where the outbreak was first detected late last year. While China had officially designated all areas of the country as low-risk last Thursday, the new cases according to data published on Sunday represent a jump from the single case reported for the day before. The new Wuhan case, the first reported in the epicentre of China's outbreak since April 3, was previously asymptomatic, according to the health commission.

Shelling of Tripoli's Mitiga airport early on Saturday, part of an intensified barrage of artillery fire on the capital in recent days, hit fuel tanks and damaged passenger planes, the Transport Ministry said in a statement. Mitiga is the last functioning airport in the Libyan capital, though civilian flights stopped in March because of repeated shelling even before the country imposed a lockdown over the coronavirus pandemic. Brega Petroleum Marketing Company, part of the National Oil Corporation, said its jet fuel tanks at Mitiga caught fire after coming under attack and firemen were working to control the blaze.

"Passing along a message from Mother Nature," the National Weather Service in Binghamton, New York, tweeted alongside a photo of a car covered in light snow. "Happy Mother's Day Weekend."

Pakistanis crowded markets on Saturday after a nationwide coronavirus lockdown was eased, despite the country declaring its second highest daily infection toll. Prime Minister Imran Khan has allowed businesses to reopen in phases from the weekend, citing the economic havoc the virus restrictions have wreaked on the improvised nation. In the garrison city of Rawalpindi, thousands of shoppers were preparing for Eid, which follows the Muslim fasting month of Ramadan, with many flouting social distancing rules and advice to wear masks.

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.

β-1,3-d-Glucan is a ubiquitous glucose polymer produced by plants, bacteria, and most fungi. It has been used as a diagnostic tool in patients with invasive mycoses via a highly-sensitive reagent consisting of the blood coagulation system of horseshoe crab. However, no method is currently available for measuring β-1,6-glucan, another primary β-glucan structure of fungal polysaccharides. Herein, we describe the development of an economical and highly-sensitive and specific assay for β-1,6-glucan using a modified recombinant endo-β-1,6-glucanase having diminished glucan hydrolase activity. The purified β-1,6-glucanase derivative bound to the β-1,6-glucan pustulan with a KD of 16.4 nm. We validated the specificity of this β-1,6-glucan probe by demonstrating its ability to detect cell wall β-1,6-glucan from both yeast and hyphal forms of the opportunistic fungal pathogen Candida albicans, without any detectable binding to glucan lacking the long β-1,6-glucan branch. We developed a sandwich ELISA-like assay with a low limit of quantification for pustulan (1.5 pg/ml), and we successfully employed this assay in the quantification of extracellular β-1,6-glucan released by >250 patient-derived strains of different Candida species (including Candida auris) in culture supernatant in vitro. We also used this assay to measure β-1,6-glucan in vivo in the serum and in several organs in a mouse model of systemic candidiasis. Our work describes a reliable method for β-1,6-glucan detection, which may prove useful for the diagnosis of invasive fungal infections.

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.

Actinobacillus pleuropneumoniae (App) is the etiological agent of acute porcine pneumonia and responsible for severe economic losses worldwide. The capsule polymer of App serotype 1 (App1) consists of [4)-GlcNAc-β(1,6)-Gal-α-1-(PO4-] repeating units that are O-acetylated at O-6 of the GlcNAc. It is a major virulence factor and was used in previous studies in the successful generation of an experimental glycoconjugate vaccine. However, the application of glycoconjugate vaccines in the animal health sector is limited, presumably because of the high costs associated with harvesting the polymer from pathogen culture. Consequently, here we exploited the capsule polymerase Cps1B of App1 as an in vitro synthesis tool and an alternative for capsule polymer provision. Cps1B consists of two catalytic domains, as well as a domain rich in tetratricopeptide repeats (TPRs). We compared the elongation mechanism of Cps1B with that of a ΔTPR truncation (Cps1B-ΔTPR). Interestingly, the product profiles displayed by Cps1B suggested processive elongation of the nascent polymer, whereas Cps1B-ΔTPR appeared to work in a more distributive manner. The dispersity of the synthesized products could be reduced by generating single-action transferases and immobilizing them on individual columns, separating the two catalytic activities. Furthermore, we identified the O-acetyltransferase Cps1D of App1 and used it to modify the polymers produced by Cps1B. Two-dimensional NMR analyses of the products revealed O-acetylation levels identical to those of polymer harvested from App1 culture supernatants. In conclusion, we have established a protocol for the pathogen-free in vitro synthesis of tailored, nature-identical App1 capsule polymers.

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.

Fucosylation of the innermost GlcNAc of N-glycans by fucosyltransferase 8 (FUT8) is an important step in the maturation of complex and hybrid N-glycans. This simple modification can dramatically affect the activities and half-lives of glycoproteins, effects that are relevant to understanding the invasiveness of some cancers, development of mAb therapeutics, and the etiology of a congenital glycosylation disorder. The acceptor substrate preferences of FUT8 are well-characterized and provide a framework for understanding N-glycan maturation in the Golgi; however, the structural basis of these substrate preferences and the mechanism through which catalysis is achieved remain unknown. Here we describe several structures of mouse and human FUT8 in the apo state and in complex with GDP, a mimic of the donor substrate, and with a glycopeptide acceptor substrate at 1.80–2.50 Å resolution. These structures provide insights into a unique conformational change associated with donor substrate binding, common strategies employed by fucosyltransferases to coordinate GDP, features that define acceptor substrate preferences, and a likely mechanism for enzyme catalysis. Together with molecular dynamics simulations, the structures also revealed how FUT8 dimerization plays an important role in defining the acceptor substrate-binding site. Collectively, this information significantly builds on our understanding of the core fucosylation process.

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.

Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.

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 U.S. refugee protection system, while generous in many respects, has become less robust over the last two decades. The unique and often diverse needs of emerging refugee populations have exposed severe limitations in the standard resettlement approach.This report examines U.S. legal and policy responses to those seeking protection and addresses the barriers, gaps, and opportunities that exist.

Drawing on experiences from Asia, Europe, North America, and the Pacific region, this report presents eight strategies that represent best practices developed by immigrant-receiving countries to increase the economic contributions of immigration.

The exponential growth of international travel since the 1960s has left border management systems worldwide struggling to keep up and has exposed weaknesses in states’ abilities to effectively manage their borders, especially regarding terrorist attacks, human trafficking, and illegal migration.

MANCHESTER, England (AP): Paul Pogba and Marcus Rashford are expected to be available for Manchester United whenever the Premier League is allowed to resume after the suspension caused by the coronavirus outbreak. Whether United manager Ole Gunnar...

Cavalier’s technical director, Rudolph Speid, says the recent positive ranking by CIES (International Centre for Sports Studies) Football Observatory, a research group based in Switzerland, is a reflection of the work the club is doing in trying to...

BRIDGETOWN, Barbados (CMC): Former top West Indies cricket administrator, 76-year-old Deryck Murray, has warned against a forced restart of cricket amid the current challenges posed by the deadly coronavirus pandemic, and says any premature actions...

THE LAST two months have been two of the worst in the life of former national netball star Nichala Gibson. She lives in New York City, the epicentre for the COVID-19 virus in the United States. Gibson and her sister suffered, then recovered from...

At least 10 stores inside the Portmore Mall have fallen casualty to the economic chokehold brought on by the COVID-19 pandemic, with several others struggling to stay afloat as St Catherine businesses grapple with revenue losses. And with a 14-day...

(AP): South Korea’s capital, Seoul, has closed down more than 2,000 bars and other nightspots because of a new cluster of COVID-19 infections; Germany scrambled to contain fresh outbreaks at slaughterhouses; and...

Jamaica is now two cases shy of 500 confirmed COVID-19 infections with the confirmation of eight new cases in the past 24 hours.  The new infections bring the total number to 498 confirmed COVID-19 cases.  In a release a short while...

This special issue focuses on The Role of Community Health Workers as First Responders in the COVID-19 Outbreak. 

Recorded May 5, 2020.

This is a part of the American Diabetes Associations ongoing project providing resources for practicing clinicians on the care of Diabetes during the Covid-19 pandemic.  Today’s discussion is an audio version of a webinar recorded on May 5, 2020.

Presented by:

Betsy Rodriguez, BSN, MSN, DCES
Centers for Disease Control and Prevention

Colleen Barbero, PhD
Centers for Disease Control and Prevention

Denise Octavia Smith, MBA, CHW, PN, SFC
National Association of Community Health Workers

This book explores how developing-country governments have institutionalized ties with emigrants and their descendents. It offers an unprecedented taxonomy of 45 diaspora-engaging institutions found in 30 developing countries, exploring their activities and objectives. It also provides important practitioner insights from Mali, Mexico, and the Philippines.

This edited volume examines the development impact of diasporas in six critical areas: entrepreneurship, capital markets, "nostalgia" trade and "heritage" tourism, philanthropy, volunteerism, and advocacy.

Este manual ofrece a los formuladores de políticas y especialistas una guía accesible y práctica sobre las iniciativas gubernamentales referentes a la diáspora. Este manual contiene un menú, seleccionado cuidadosamente, de opciones normativas y programáticas viables basadas en experiencias reales en distintas partes del mundo.

Ce manuel pratique et simple d’utilisation à l’usage des décideurs et des praticiens fait le point des mesures les plus récentes prises par les pouvoirs publics en direction des diasporas. La question qui se pose aux responsables politiques n’est pas tant de savoir si les diasporas peuvent être utiles à leur pays d’origine, mais comment elles le sont et quels types de politiques et de programmes publics sont à même de favoriser ces relations.

This practical handbook highlights policies and programs that can magnify the resources, both human and financial, that emigrants and their descendants contribute to development. It gives concrete examples of policies and programs that have been effective, and pulls out both useful lessons and common challenges associated with the topics at hand.

This edited volume develops a pragmatic approach to the engagement of highly skilled members of the diaspora for the benefit of their countries of origin. The book, edited by a World Bank senior economist, is based on empirical work in middle-income and high-income economies.

This edited volume showcases approaches toward border management in Europe, Central America, and North America, and reflects on the challenges that countries in these regions face in managing their borders. The book brings together perspectives from both sides of the Atlantic on what border security means in practice, the challenges that continue to evade policymakers, and what policies have been the most (and least) successful in achieving “secure” borders.

The enactment of President Clinton’s Limited English Proficiency (LEP) Executive Order, issued in 2000, triggered a proliferation of efforts to provide services to individuals who cannot speak, understand, read, or write English fluently. With increased service provision, state and local government agencies have expressed a strong and growing interest in assuring the quality and cost-effectiveness of language access services. This paper attempts to catalog and describe some of those tools and practices.

Public Policy Institute of California researchers Magnus Lofstrom and Laura Hill discuss their research examining the potential labor market outcomes and other possible economic effects of a legalization program.