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.

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

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.

Noncoercive, pay-to-go, voluntary, assisted voluntary, and nonforced returns generally can offer paid travel and/or other financial incentive to encourage unauthorized immigrants to cooperate with immigration officials and leave host countries. A look at three key rationales for governments to choose pay-to-go and other returns.

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.

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.

Since 1970, the immigrant populations from Mexico and Central America living in the United States have increased significantly: rising by a factor of 20 even as the total U.S. immigrant population increased four-fold over the period. This demographic report examines the age, educational, and workforce characteristics of these immigrants.

Showcasing joint research by MPI and the European University Institute and funded by the European Commission, this event featured discussion on some of the most promising reform proposals on both sides of the Atlantic. Speakers discuss the project’s comparative research, which draws on MPI’s longstanding experience advising European and North American governments on immigration.

This final report summarizes and reflects upon the key findings of the Improving EU and U.S. Immigration Systems: Learning from Experience comparative research project undertaken by MPI and the European University Institute through a grant from the European Commission.

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...

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...

A Manchester corporal is now on sick leave after receiving several blows to his face allegedly by a woman police inspector at work yesterday. It is reported that the incident happened in the guard room of the Mandeville Police Station.

When siblings Norma and Warren Williams left Jamaica to attend the funeral of a relative in Margate, South Florida, in February, they had no idea that a rapidly developing COVID-19 outbreak would have crippled global travel, leaving them stranded...

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...

Almost five years ago, lawmakers on a bipartisan committee of Parliament agreed unanimously to amend the law to give the Independent Commission of Investigations (INDECOM) the power to arrest and prosecute cops. That proposed amendment, which was...

This report analyzes prenatal behaviors and birth outcomes of Black immigrant mothers, and finds that Black immigrant mothers are less likely to give birth to preterm or low-birth-weight infants than U.S.-born Black women, but more likely to experience these birth outcomes than other immigrant and U.S.-born women.

This report focuses on the development of children of Black immigrants in the United States, comparing against the outcomes for their peers in native-born and other immigrant families. It also compares these U.S. children to those in the United Kingdom, where there is a large Black immigrant population but a notably different policy context of reception.

This report draws on a six-year longitudinal study of Palm Beach County, FL, examining parenting, child care enrollment, and other factors that encourage early school success. The authors find kindergarten-age children of Black immigrants have significantly higher odds of being ready for school than children of Latina immigrant or Black U.S.-born mothers.

MPI’s National Center on Immigrant Integration Policy convened a major public policy research symposium focused on young children of immigrants in the U.S.

Last Thursday morning, I went to visit my youngest grandchild, three-year-old Morgan. As she emerged from her bedroom with her tablet in hand and a scream on her lips then saw me and barged towards me, I knew that a full embrace was not going to...

ADVISORY COLUMN: PERSONAL FINANCIAL ADVISER QUESTION: I looked through The Gleaner and saw a response you gave to a question. I realise that most of the housing developments around are superexpensive, so my wife and I are thinking of purchasing...

The operator Jamaica’s two largest airports wants to scrap or delay non-essential capital projects. It forms part of a wider halt of capital projects by the Grupo Aeroportuario del Pacífico – which translate to Pacific Airport Group, or GAP –...

Car-rental companies in Jamaica are facing a serious crush, with at least one medium player looking to shut down operations, and others, big and small, saying that they are barely holding on. The collapse in the vacation market and travel...

Health Minister Dr Christopher Tufton and a 70-member team of healthcare workers are now in Dover, St Mary where they have been conducting house to house visits to test persons for COVID-19.  They have also been providing health...

(AP): Many people saw more than the last moments of Ahmaud Arbery’s life when a video emerged this week of white men armed with guns confronting the black man; a struggle with punches thrown; three shots fired and Arbery collapsing...

(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...

There is nothing average about Bishop Cleveland Mattis who uses the skills and knowledge he has acquired over the years, from varying areas, to be more relatable to the people he serves and transform lives through the teachings of the Holy Spirit...

The common questions that many are asking today in relation to the COVID-19 pandemic are: Why has this befallen us? Why is there so much death and dying from this disease? Where is God in all of this? If God exists, why doesn’t He intervene and...

The coronavirus pandemic (COVID-19) has resulted in many opportunities for the health technology industry. Our usually technophobic population has been embracing technology more and more since the start of the restrictions due to the spread of...

Education officials across the Caribbean and Latin America have asserted that teachers will be in need of psycho-social support for their return to the classroom, following the COVID-19 pandemic. Approximately 91,710 teachers and seven million...

Lady Allen – wife of Jamaica’s Governor General Sir Patrick Allen – says Jamaican women are among the strongest and most resilient in the world, and despite many bearing the full brunt of the coronavirus pandemic as breadwinners for their families...

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