Cholesteryl ester transfer protein (CETP) exists as full-length (FL) and exon 9 (E9)-deleted isoforms. The function of E9-deleted CETP is poorly understood. Here, we investigated the role of E9-deleted CETP in regulating the secretion of FL-CETP by cells and explored its possible role in intracellular lipid metabolism. CETP overexpression in cells that naturally express CETP confirmed that E9-deleted CETP is not secreted, and showed that cellular FL- and E9-deleted CETP form an isolatable complex. Coexpression of CETP isoforms lowered cellular levels of both proteins and impaired FL-CETP secretion. These effects were due to reduced synthesis of both isoforms; however, the predominate consequence of FL- and E9-deleted CETP coexpression is impaired FL-CETP synthesis. We reported previously that reducing both CETP isoforms or overexpressing FL-CETP impairs cellular triglyceride (TG) storage. To investigate this further, E9-deleted CETP was expressed in SW872 cells that naturally synthesize CETP and in mouse 3T3-L1 cells that do not. E9-deleted CETP overexpression stimulated SW872 triglyceride synthesis and increased stored TG 2-fold. Expression of E9-deleted CETP in mouse 3T3-L1 cells produced a similar lipid phenotype. In vitro, FL-CETP promotes the transfer of TG from ER-enriched membranes to lipid droplets. E9-deleted CETP also promoted this transfer, although less effectively, and it inhibited the transfer driven by FL-CETP. We conclude that FL- and E9-deleted CETP isoforms interact to mutually decrease their intracellular levels and impair FL-CETP secretion by reducing CETP biosynthesis. E9-deleted CETP, like FL-CETP, alters cellular TG metabolism and storage but in a contrary manner.

When you read in a BigQuery table, the length of string variables might be longer than the length specified with the MAX_CHAR_LEN= option when running your SAS software   with UTF-8. By

Monogenic forms of obesity have been identified in ≤10% of severely obese European patients. However, the overall spectrum of deleterious variants (point mutations and structural variants) responsible for childhood severe obesity remains elusive. In this study, we genetically screened 225 severely obese children from consanguineous Pakistani families through a combination of techniques including an in-house developed augmented whole-exome sequencing (CoDE-seq) enabling simultaneous detection of whole exome copy number variations (CNVs) and of point mutations in coding regions. We identified 110 probands (49%) carrying 55 different pathogenic point mutations and CNVs in 13 genes/loci responsible for non-syndromic and syndromic monofactorial obesity. CoDE-seq also identified 28 rare or novel CNVs associated with intellectual disability in 22 additional obese subjects (10%). Additionally, we highlight variants in candidate genes for obesity warranting further investigation. Altogether, 59% of the studied cohort are likely to have a discrete genetic cause with 13% of these due to CNVs demonstrating a remarkably higher prevalence of monofactorial obesity than hitherto reported and a plausible over lapping of obesity and intellectual disabilities in several cases. Finally, inbred populations with high prevalence of obesity, provide a unique genetically enriched material in quest of new genes/variants influencing energy balance.

Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin–Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor–like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies.

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.

Gunnar Stenström
Dec 1, 2005; 54:S68-S72
Section II: Type 1-Related Forms of Diabetes

6 November 2019 , Volume 95, Number 6

Research Event

Event participants

Emerging film-makers will have the opportunity to produce a short film based on the theme ‘My Windrush Story – What Windrush Means to Me’ as part of the Windrush Caribbean Film Festival (WCFF), which will be held later this year as part of Black...

23 October 2019

Invitation Only Research Event

Event participants

Archbishop Yevstraty (Zoria) of Chernihiv, Deputy Head of Department for External Church Relations, Ukrainian Orthodox Church (Orthodox Church of Ukraine)

21 January 2020

Invitation Only Research Event

Event participants

Maia Sandu, President, Action and Solidarity Party; Prime Minister of Moldova (June-November 2019)
Chair: Cristina Gherasimov, Research Fellow, German Council on Foreign Relations; Academy Associate, Russia and Eurasia Programme, Chatham House
 

Invitation Only Research Event

Event participants

Invitation Only Research Event

REGGAE ARTISTE Isha Blender is still coming to terms with the loss of her son, Josiah, on January 5, a mere two days after she celebrated her birthday. The daughter of legendary crooner Everton Blender said the death of a child can be one of the...

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...

Looking after a young child is hard enough, but when that child has learning difficulties and displays challenging behaviour - the burden on parents can be extreme. That behaviour may prompt a visit to the doctor, and in this podcast we’re talking about how parents can be supported in that - what services are available. We’ll also be discussing...

Precocious puberty, that is puberty that starts before age 8 in girls and 9 in boys seems to be on the rise, but whether that’s because of an increase in incidence, or greater attention is unknown - what we do know that precocious puberty in girls is commonly idiopathic, while in boys is a red flag for pathology. But either way ther first point of...

Charles M. Alexander
May 1, 2003; 52:1210-1214
Complications

Lipodystrophies are a group of disorders characterized by absence or loss of adipose tissue and abnormal fat distribution, commonly accompanied by metabolic dysregulation. Although considered rare disorders, their prevalence in the general population is not well understood. We aimed to evaluate the clinical and genetic prevalence of lipodystrophy disorders in a large clinical care cohort. We interrogated the electronic health record (EHR) information of >1.3 million adults from the Geisinger Health System for lipodystrophy diagnostic codes. We estimate a clinical prevalence of disease of 1 in 20,000 individuals. We performed genetic analyses in individuals with available genomic data to identify variants associated with inherited lipodystrophies and examined their EHR for comorbidities associated with lipodystrophy. We identified 16 individuals carrying the p.R482Q pathogenic variant in LMNA associated with Dunnigan familial partial lipodystrophy. Four had a clinical diagnosis of lipodystrophy, whereas the remaining had no documented clinical diagnosis despite having accompanying metabolic abnormalities. We observed a lipodystrophy-associated variant carrier frequency of 1 in 3,082 individuals in our cohort with substantial burden of metabolic dysregulation. We estimate a genetic prevalence of disease of ~1 in 7,000 in the general population. Partial lipodystrophy is an underdiagnosed condition. and its prevalence, as defined molecularly, is higher than previously reported. Genetically guided stratification of patients with common metabolic disorders, like diabetes and dyslipidemia, is an important step toward precision medicine.

19 December 2014

This research paper sets out recommendations for enhanced dialogue and intensified international cooperation that could significantly improve the functioning of global mineral markets.

Members Event

Event participants

Rory Stewart, Member of Parliament for Penrith and The Border (2010-19); Secretary of State for International Development (2019)

Chair: Daniel Bruce, Chief Executive, Transparency International UK

Members Event

Event participants

HE George Vella, President, Republic of Malta

Chair: Dr Alex Vines OBE, Managing Director, Ethics, Risk & Resilience; Director, Africa Programme, Chatham House

Members Event Webinar

Event participants

Dr Catherine Howe, Director, Democracy Society

Hans Kundnani, Senior Research Fellow, Europe Programme, Chatham House

Chair: Thomas Raines, Director, Europe Programme, Chatham House

Invitation Only Research Event

Event participants

Dr Murat Ucer, Turkey Country Analyst, GlobalSource Partners 
Chair: Fadi Hakura, Manager, Turkey Project, Europe Programme, Chatham House

Approximately 11,500 unaccompanied children were apprehended at the U.S.-Mexico border in May, putting this year on track to exceed 2014's surge. As the U.S. government struggles to care for these child migrants, with public outrage mounting over reports of unsafe, filthy conditions in initial Border Patrol custody, the failure of the executive branch and Congress to plan for increased shelter and care demands are increasingly apparent, as this article explores.

Having emerged from a long era of military rule, Myanmar's leaders and many citizens are looking outward. In particular, with Burmese labor migration abroad on the rise, policymakers are examining ways in which to harness remittances as a vehicle for economic development, particularly in impoverished rural areas. This article explores Burmese labor migration flows, financial reforms, and challenges on migration and development.

For generations, migrants have emigrated from Senegal, particularly from in and around the Senegal River Valley. With France a key destination, French policy changes have had significant impact on Senegalese migrants and the hometown associations through which they support development in Senegal. This article explores how these policy shifts influence development and quality of life in the Senegal River Valley.

The Member States of the United Nations convened in December to adopt the Global Compact for Safe, Orderly, and Regular Migration (GCM). Ahead of the adoption, this side event in Marrakech (open only to those with GFMD credentials) considered the coordination and mechanisms most needed to achieve the commitments laid out in the GCM.

Colombia has more internally displaced persons (IDPs) than any other country in the world, the result of a 52-year civil war. Beyond improving the lives of its 7.3 million IDPs, the country faces a number of crucial migration issues as it works to achieve stability in the wake of an historic peace accord signed in late 2016. This country profile examines historical trends and current and future migration challenges in Colombia.

Nearly 6 million Afghans fled after violence erupted in the late 1970s, primarily to Iran and Pakistan. While millions returned after the collapse of the Taliban in 2001, the security situation has since deteriorated and the government struggles to meet the needs of vulnerable populations, particularly the internally displaced. This country profile explores Afghanistan’s complex migration and displacement history as well as ongoing challenges.

El Salvador is the smallest country in Central America yet the most densely populated. A stagnant economy, high levels of crime and violence, and natural disasters have pushed growing numbers of people to migrate without authorization or seek asylum abroad, mostly in the United States. This article explores historical and contemporary emigration from El Salvador.

The Netherlands has witnessed a rise in far-right populism, challenging its reputation as a humanitarian haven. Yet, public fears equating immigration with a rise in religious extremism do not necessarily reflect the facts. This profile explores historical and contemporary migration in a country where population growth relies largely on immigration, and analyzes to what extent policymaking has been shaped by rising populism.

This report summarizes the economic and social development policy achievements of Central American countries over the past 20 years, as well as the notable obstacles to development that remain. The author identifies long-term challenges and outlines how they can be incorporated into a new development agenda.

Nearly 4 million South Sudanese have been driven from their homes by violence or food insecurity since late 2013, roughly half seeking refuge in neighboring countries. Drought and conflict have converged in the young country to fuel one of the world's most severe humanitarian emergencies. This article examines refugee flows from South Sudan, underlying drivers, and regional and international responses to the crisis.

While skilled migration brings widely acknowledged economic benefits for destination countries and migrants, its impact on countries of origin has been the subject of more debate. Despite a growing consensus that origin countries can benefit from emigration and the circulation of skills, enabling this potential to be fully exploited remains a challenge. This report examines initiatives that develop skills and human capital.

This report by MPI and the Asian Development Bank lays out a realistic roadmap toward freer movement among skilled professionals within the ASEAN Economic Community (AEC), encouraging cooperation among ASEAN Member States in recognizing foreign qualifications and making government investments in training and educations systems that prepare workers in accordance with common standards.

OBJECTIVE

Dysglycemia, in this survey defined as impaired glucose tolerance (IGT) or type 2 diabetes, is common in patients with coronary artery disease (CAD) and associated with an unfavorable prognosis. This European survey investigated dysglycemia screening and risk factor management of patients with CAD in relation to standards of European guidelines for cardiovascular subjects.

Lisa S. Rotenstein
Oct 1, 2012; 30:138-150
Features

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.

Ideological differences in the Democratic Party over immigration that were once masked by unity against President Trump’s border wall and immigration agenda are now being exposed as Democratic presidential candidates seek to stand out in a crowded field and amid controversy over an emergency border spending bill. As the 2020 electoral calendar accelerates, how the party navigates the gulf between its most liberal and conservative wings will become a greater challenge for its leaders.