WASHINGTON (March 3, 2020) — Today, the U.S. Environmental Protection Agency (EPA) announced a supplemental notice of proposed rulemaking to the Strengthening Transparency in Regulatory Science proposed rule.

WASHINGTON (April 2, 2020) Today, the U.S. Environmental Protection Agency (EPA) announced an extension of the comment period on the supplemental notice of proposed rulemaking for the proposed rule, “Strengthening Transparency in Regulatory Science.”

WASHINGTON (April 28, 2020) —  Today, the U.S. Environmental Protection Agency’s (EPA) Science Advisory Board (SAB) transmitted its official advice and comments to EPA Administrator Wheeler on the Strengthening Transparency in Regulatory Science proposed rule.

(MEXICO CITY) – Today, U.S. Environmental Protection Agency Administrator Andrew Wheeler wrapped up trilateral meetings with Canada and Mexico as part of the 25th Anniversary of the Commission for Environmental Cooperation (CEC) Council meetings in Mexico City.

When a famed Egyptian actor revealed his daughter had transitioned, the reaction was unconventional.

Manchester United and Everton have been put on alert by the news that Juventus midfielder Adrien Rabiot is willing to move to the Premier League.

The DML News App offers the best in news reporting.

The post REPORT: Here’s What Comey Told Congress About Whether Flynn Lied To FBI: Transcript appeared first on Dennis Michael Lynch.

8 November 2013

Invitation Only Research Event

Event participants

Dr Leena Koni Hoffmann, Centre for Population, Poverty and Public Policy Studies; Author, Who Speaks for the North? Politics and Influence in Northern Nigeria; ERANDA Junior Research Fellow, Africa Programme, Chatham House (2013)
Chair: Elizabeth Donnelly, Assistant Head, Africa Programme, Chatham House

Research Event

Event participants

Christopher K Johnson, Senior Adviser; Freeman Chair in China Studies, Center for Strategic and International Studies
Chair: Dr Michal Meidan, Associate Fellow, Asia Programme, Chatham House 

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.

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.

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.

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.

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.

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.

The EU-U.S. relationship is one of the most significant partnerships among wealthy nations. Interconnections between the two on migration issues make dialogue necessary and inevitable, as each relies on each other to attain a number of policy objectives, most clearly in the case of travel and border security.

This edited volume addresses the impact of the economic crisis in seven major immigrant-receiving countries: the United States, Germany, Ireland, Portugal, Spain, Sweden, and the United Kingdom. 

This report provides an overview of several commonly used translation and interpretation technologies. It aims to assist language access practitioners in understanding and identifying which systems would best meet their agency’s language access needs.

The release event for MPI’s book, Migration and the Great Recession: The Transatlantic Experience, which reviews how the financial and economic crisis of the late 2000s marked a sudden and dramatic interruption in international migration trends, and the effects of the economic turmoil on immigrant workers in major immigrant-receiving countries in Europe as well as the United States.

I'll try to keep this short: So I have always dated guys. Yet when I am not dating guys, my best friend and I; who's a girl, hook up. We've been doing this for about 5 years, we met at the age of 15, and 5 yrs later I had my first lesbian experience with her, and then 5 years it became a fairly regular thing. 5 years is obviously a long time. But when I'm not dating a guy, I always go back to her. And she's the only woman I have ever been with. That's why I am confused about this. I do not know if I'm straight or a lesbian?

Testimony of Andrew Selee, President of MPI, before the Senate Judiciary Committee's Subcommittee on Border Security and Immigration on December 12, 2018 regarding the intersections of transnational crime, immigration, and border security.

A new program is giving bicycles to Indigenous youth who move to Winnipeg for school to help them get around the city as they pursue their studies.

Chronic rejection of transplanted organs is the leading cause of transplant failure, and one that the field of organ transplantation has not overcome in almost six decades since the advent of immunosuppressive drugs enabled the field to flourish.

Tim and Sophie, an Australian couple with OM in Paris, experienced life in North Africa, and its many different needs and difficulties, through Transform 2012.

How God called Andrea from Italy to leave his comfort zone during the Transform conference and his experience with OM Lifehope in the UK.

Participating in a Transform outreach to trafficked women gave OMer Erika Tello the vision of founding the OM Italy anti-trafficking ministry.

Cyclists with the Ride to Transform initiative rode 830 kilometres (about 515 miles) through Italy to raise funds for Transform relief projects around the Mediterranean.

Around 340 people participated in the Transform 2013 mission conference in Rome before spreading across the Mediterranean on 29 outreaches.

Artists participating in the Incarnate training and discipleship programme of OM Arts in Italy are inspired by conversations with locals.

Meeting Christian refugees praying for European governments made a deep impression on a Transform participant. For another, the term ‘refugee’ got a whole new meaning.

Two OM workers share the gospel while riding on buses in Turkey.

OM Russia's short-term outreach team travels across Russia sharing about Christ with as many travellers as possible.

A team member from the USA who participated in a short-term trip on the Trans-Siberian railroad across Russia shares her experience.

A Greek woman embarks on a lonely journey to the Transform 2013 conference in Rome, a journey that began when she accepted Christ at 19.

After attending Transform 2014 and going on the Greece outreach, a young South African man returns to Greece eight months later to stay.

God is working to transform lives in Mozambique through the efforts of the local OM team.

Walking the thousand year old pilgrim route to Santiago de Compostela gave the Transform team many opportunities to share the Gospel

Participants witnessed God at work through the Transform conference in Spain followed by outreach teams to the Mediterranean region and beyond.

Newlyweds Sam & Lena joined Transform as part of their honeymoon, because they wanted to honour God from the very start of their life together.

The OM Transform team experienced God at work during the conference and outreach day. The local churches were an added blessing, as was the cycling team sent out to pray for least reached towns.

Transform mission conference one year, outreach team in France the following year, the sisters from Mexico are eager to share the love of Christ, realising the audience was different from what they expected.

It started with one ball and grew to become a garden.

A young woman's life is transformed by the love of Jesus shared and displayed through Tabitha Skills Training in Zambia.

OM Lifehope coordinates the Transit Challenge, sending out teams all over Europe to love, serve and proclaim Christ.

An OM training conference equips a local pastor with tools to transform his Sunday service for Syrian refugees.

Ofentse Mokwena discusses what's needed for opening transport markets and unbundling transport SOEs.