Individuals with Netherton syndrome (NTS) have increased serine protease activity, which strongly impacts the barrier function of the skin epidermis and leads to skin inflammation. Here, we investigated how serine protease activity in NTS correlates with changes in the stratum corneum ceramides, which are crucial components of the skin barrier. We examined two key enzymes involved in epidermal ceramide biosynthesis, glucocerebrosidase (GBA) and acid-sphingomyelinase (ASM). We compared in situ expression levels and activities of GBA and ASM between NTS patients and controls and correlated the expression and activities with i) stratum corneum ceramide profiles, ii) in situ serine protease activity, and iii) clinical presentation of patients. Using activity-based probe labeling, we visualized and localized active, epidermal GBA, and a newly developed in situ zymography method enabled us to visualize and localize active ASM. Reduction in active GBA in NTS patients coincided with increased ASM activity, particularly in areas with increased serine protease activity. NTS patients with scaly erythroderma exhibited more pronounced anomalies in GBA and ASM activities than patients with ichthyosis linearis circumflexa. They also displayed a stronger increase in stratum corneum ceramides processed via ASM. We conclude that changes in the localization of active GBA and ASM correlate with i) altered stratum corneum ceramide composition in NTS patients, ii) local serine protease activity, and iii) the clinical manifestation of NTS. 

The presentation of post-translationally modified (PTM) peptides by cell surface HLA molecules has the potential to increase the diversity of targets for surveilling T cells. Whilst immunopeptidomics studies routinely identify thousands of HLA-bound peptides from cell lines and tissue samples, in-depth analyses of the proportion and nature of peptides bearing one or more PTMs remains challenging. Here we have analyzed HLA-bound peptides from a variety of allotypes and assessed the distribution of mass spectrometry-detected PTMs, finding deamidation of asparagine or glutamine to be highly prevalent. Given that asparagine deamidation may arise either spontaneously or through enzymatic reaction, we assessed allele-specific and global motifs flanking the modified residues. Notably, we found that the N-linked glycosylation motif NX(S/T) was highly abundant across asparagine-deamidated HLA-bound peptides. This finding, demonstrated previously for a handful of deamidated T cell epitopes, implicates a more global role for the retrograde transport of nascently N-glycosylated polypeptides from the ER and their subsequent degradation within the cytosol to form HLA-ligand precursors. Chemical inhibition of Peptide:N-Glycanase (PNGase), the endoglycosidase responsible for the removal of glycans from misfolded and retrotranslocated glycoproteins, greatly reduced presentation of this subset of deamidated HLA-bound peptides. Importantly, there was no impact of PNGase inhibition on peptides not containing a consensus NX(S/T) motif. This indicates that a large proportion of HLA-I bound asparagine deamidated peptides are generated from formerly glycosylated proteins that have undergone deglycosylation via the ER-associated protein degradation (ERAD) pathway. The information herein will help train deamidation prediction models for HLA-peptide repertoires and aid in the design of novel T cell therapeutic targets derived from glycoprotein antigens.

1 January 2007 , Number 2

For all the cynicism it has evoked, the United States’ Iraq Study Group report might still lead to a regional diplomatic process, which could ease Iran and the US into negotiations. A grand bargain is very unlikely, but with Washington at the table, there might be enough advantage for both sides in a gradual process to halt the current slide towards a deeper confrontation.

Ceramides (Cers) with ultralong (~32-carbon) chains and -esterified linoleic acid, composing a subclass called omega-O-acylceramides (acylCers), are indispensable components of the skin barrier. Normal barriers typically contain acylCer concentrations of ~10 mol%; diminished concentrations, along with altered or missing long periodicity lamellar phase (LPP), and increased permeability accompany an array of skin disorders, including atopic dermatitis, psoriasis, and ichthyoses. We developed model membranes to investigate the effects of the acylCer structure and concentration on skin lipid organization and permeability. The model membrane systems contained six to nine Cer subclasses as well as fatty acids, cholesterol, and cholesterol sulfate; acylCer content—namely, acylCers containing sphingosine (Cer EOS), dihydrosphingosine (Cer EOdS), and phytosphingosine (Cer EOP) ranged from zero to 30 mol%. Systems with normal physiologic concentrations of acylCer mixture mimicked the permeability and nanostructure of human skin lipids (with regard to LPP, chain order, and lateral packing). The models also showed that the sphingoid base in acylCer significantly affects the membrane architecture and permeability and that Cer EOP, notably, is a weaker barrier component than Cer EOS and Cer EOdS. Membranes with diminished or missing acylCers displayed some of the hallmarks of diseased skin lipid barriers (i.e., lack of LPP, less ordered lipids, less orthorhombic chain packing, and increased permeability). These results could inform the rational design of new and improved strategies for the barrier-targeted treatment of skin diseases.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

Members Event Webinar

Emanuela-Chiara Gillard, Associate Fellow, International Law Programme, Chatham House

Chair: Chanu Peiris, Programme Manager, International Law Programme, Chatham House

Further speakers to be announced.

Invitation Only Research Event

Event participants

Dr Kori Schake, Resident Scholar and Director of Foreign and Defense Policy Studies, American Enterprise Institute 
Chair: Dr Leslie Vinjamuri, Director, US and Americas Programme

I hear God in cushion prints, Leopard pants, Ancestors, We Forget; What if it took place at midnight, would you Stack hay and win, Chicago with the broad shoulders, Hunt mosquitos, Midnight lover, the Ebullient wrestler in a, Pink Venetian mask, Would you, Be a brute, Pretending the contender was not God, Brisk breeze, Be […]

By the month of May in any given year, the many and varied events and competitions staged by the Jamaica Cultural Development Commission (JCDC) islandwide would have been in high gear. Each year the JCDC rolls out its much-anticipated menu board...

Between December 2019 and February 2020, The Gleaner published a series of articles on my behalf, exploring the issue of food security in Jamaica based on an analysis of the country’s food-import bill for 2018. The current COVID-19 pandemic, which...

Public reaction to the initial threat of the coronavirus (COVID-19) was predictably mixed. While international news of the contagion across continents helped people to appreciate that this was not restricted to a particular region, not many people...

Middle East respiratory syndrome (MERS) is an acute viral respiratory tract infection caused by the novel betacoronavirus. Cases have been limited to the Arabian Peninsula and its surrounding countries, and to travellers from the Middle East or their contacts. The clinical spectrum of infection varies from no symptoms or mild respiratory...

Director of the Pan American Health Organization (PAHO), Carissa Etienne, today urged for vaccination programmes to continue during the COVID-19 pandemic. “If we fall behind on routine immunisations, particularly for children, we risk...

The Bundesliga -- Germany's top soccer league -- will be allowed to resume in May after German Chancellor Angela Merkel lifted some lockdown restrictions in the country on Wednesday amid the coronavirus pandemic.

A limited number of fans will be allowed to enter ballparks for games in Taiwan for the first time this season as stay-at-home orders continue to loosen amid the coronavirus pandemic.

OBJECTIVE

Diabetes is a rapidly growing health problem in low- and middle-income countries (LMICs), but empirical data on its prevalence and relationship to socioeconomic status are scarce. We estimated diabetes prevalence and the subset with undiagnosed diabetes in 29 LMICs and evaluated the relationship of education, household wealth, and BMI with diabetes risk.

The Air Force and Marines have both reported engaging in training maneuvers in the East and South China Sea in recent weeks amid escalating tensions in the region.

The high-stakes gambit taken by Turkish President Recep Tayyip Erdoğan to allow tens of thousands of asylum seekers and migrants free movement to the Greek border demonstrated the fragility of the EU-Turkey deal and the European Union's broader approach to outsource migration management to third countries. This article examines the causes for the tensions, the EU approach to external partnerships, and a hardening European attitude towards unwanted arrivals.

The Connecticut Foundation for Dental Outreach has postponed the Connecticut Mission of Mercy Free Dental Clinic scheduled for March 20-21 in Danbury, Connecticut, "out of abundant caution" amid the coronavirus disease outbreak.

Wisconsin dentists have answered the call for personal protective equipment by organizing drives and donating their surplus supplies to hospitals and urgent care facilities treating patients with COVID-19.

Two additional Delta Dental member companies announced details April 27-28 of programs that will provide economic assistance and post-COVID-19 pandemic relief for members of its independent provider networks across 16 states and the District of Columbia.

Oil prices were higher early Tuesday amid renewed concern about Venezuelan supplies but market worries about China-U.S. trade issues prevented higher gains.

Oil prices rose Wednesday amid expectations that Venezuelan oil shipments would see some disruption following U.S. sanctions.

Oil prices rose early Friday amid supply concerns following reports of smaller-than-expected stocks, and amid reduced expectation of interest rate hikes.

BP on Friday announced plans to increase disclosure on its efforts to fight climate change after requests from two groups of investors.

OBJECTIVE

To identify sleep duration trajectories from early to middle adulthood and their associations with incident type 2 diabetes.

OBJECTIVE

Acrylamide exposure from daily-consumed food has raised global concern. We aimed to assess the exposure-response relationships of internal acrylamide exposure with oxidative DNA damage, lipid peroxidation, and fasting plasma glucose (FPG) alteration and investigate the mediating role of oxidative DNA damage and lipid peroxidation in the association of internal acrylamide exposure with FPG.

MPI has released a major study that describes and analyzes today’s immigration enforcement programs, as they have developed and grown in the 25 years since IRCA launched the current enforcement era.

Release of a major report that describes and analyzes the immigration enforcement system in the United States as it has developed and grown in the quarter century since the Immigration Reform and Control Act of 1986 launched the current era of enforcement.

Record number of Venezuelans are emigrating to escape the country's economic mismanagement, insecurity, and shortages. This article examines the causes of the current crisis and draws from a study of thousands of Venezuelans abroad to examine who is leaving, where they have headed, and what their hopes are for the future of Venezuela. It also scopes future opportunities for diaspora engagement.

New Zealand drew global attention for its unity and support for the Muslim community targeted during the horrific Christchurch attacks. Yet the country's road to inclusion has been far from straightforward, and amid rising diversity it is grappling with the best way to achieve inclusion for its multiethnic population, including indigenous Māori peoples and migrants. This article outlines the opportunities and challenges to fostering multiculturalism against a backdrop of bicultural policies.

This event hosted by MPI Europe and the Research Unit of the Expert Council of German Foundations on Integration and Migration featured a discussion of research into legal migration pathways for work and training for low- and middle-skilled migrants.

Border closures and lockdowns amid the COVID-19 pandemic have put a chill on intra-EU labor mobility, most immediately with the difficulty for European farmers to gain access to much-needed seasonal workers and for health-care institutions to get care workers. This article explores how these workers, who often face difficult situations, may be more vulnerable now. It also takes on implications for intra-EU labor mobility post-pandemic.

BRUSSELS — While the European Union has called on Member States to expand channels for foreign workers as a way to meet labour market needs and potentially tackle spontaneous migration, they have struggled to deliver on this pledge. To date, policies have focused more on attracting high-skilled workers, but less attention has been paid to admission of low- or middle-skilled nationals. Policymakers would do well not to overestimate the potential of legal channels to reduce irregular migration.

WASHINGTON – Even as governments in Latin America and the Caribbean have taken generous and innovative steps to address forced displacement from Venezuela and more recently Nicaragua, the warm welcome has cooled in places amid the vast scale of the inflows, strains on public services and growing public concern.

WASHINGTON – As more than 33 million U.S. workers have lost their jobs since March amid the pandemic-induced economic crisis, immigrants are among the most vulnerable: They are more likely than the U.S. born to be laid off and to live in communities with high COVID-19 infection rates, and less likely to have health insurance coverage and access to a doctor or other usual source of health care.

This event hosted by MPI Europe and the Research Unit of the Expert Council of German Foundations on Integration and Migration featured a discussion on research into legal migration pathways for work and training for low- and middle-skilled migrants.

At least four Kentucky school districts were forced to close last Thursday as hundreds of teachers called in sick to continue protesting what they believe to be anti-public education proposals in the state legislature.

Michael Sentance, who would oversee ESSA implementation as state superintendent, is less than a year into the job and under fire by the state board for his communication and leadership style.

State education officials are responding to a state law passed last year requiring them to solicit feedback from the community on the impact of implementing later school start times for middle and high school students.