Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome

Donnai-Barrow syndrome (DBS) is an autosomal-recessive disorder characterized by multiple pathologies including malformation of forebrain and eyes, as well as resorption defects of the kidney proximal tubule. The underlying cause of DBS are mutations in LRP2, encoding the multifunctional endocytic receptor megalin. Here, we identified a unique missense mutation R3192Q of LRP2 in an affected family that may provide novel insights into the molecular causes of receptor dysfunction in the kidney proximal tubule and other tissues affected in DBS. Using patient-derived induced pluripotent stem cell lines we generated neuroepithelial and kidney cell types as models of the disease. Using these cell models, we documented the inability of megalinR3192Q to properly discharge ligand and ligand-induced receptor decay in lysosomes. Thus, mutant receptors are aberrantly targeted to lysosomes for catabolism, essentially depleting megalin in the presence of ligand in this affected family

An Endocytic Pathway Essential for Renal Uptake and Activation of the Steroid 25-(OH) Vitamin D3

AbstractSteroid hormones may enter cells by diffusion through the plasma membrane. However, we demonstrate here that some steroid hormones are taken up by receptor-mediated endocytosis of steroid-carrier complexes. We show that 25-(OH) vitamin D3 in complex with its plasma carrier, the vitamin D–binding protein, is filtered through the glomerulus and reabsorbed in the proximal tubules by the endocytic receptor megalin. Endocytosis is required to preserve 25-(OH) vitamin D3 and to deliver to the cells the precursor for generation of 1,25-(OH)2 vitamin D3, a regulator of the calcium metabolism. Megalin−/− mice are unable to retrieve the steroid from the glomerular filtrate and develop vitamin D deficiency and bone disease

Nonstandard Employment in the Nordics : Toward Precarious Work?

This article examines nonstandard employment and precariousness in four Nordic countries (Denmark, Sweden, Finland and Norway). Drawing on data from the Labour Force Survey from 1995 to 2015, the article investigates and compares recent developments of nonstandard employment in the countries and analyzes whether fixed-term contracts, temporary agency work, marginal part-time work and solo self-employment have precarious elements (measured as income or job insecurity). We conclude that nonstandard employment has remained rather stable in all four countries over time. However, although nonstandard employment seems to be largely integrated in the Nordic labor markets, it still entails precarious elements in certain countries in particular. Norway and Denmark stand out as having less insecure labor markets, while Finland and Sweden have more precariousness associated with nonstandard employment. We argue that these differences are explained by differences in the institutional contexts in the countries

Cysticercosis-related Deaths, California

Cysticercosis is an increasingly important disease in the United States, but information on the occurrence of related deaths is limited. We examined data from California death certificates for the 12-year period 1989–2000. A total of 124 cysticercosis deaths were identified, representing a crude 12-year death rate of 3.9 per million population (95% confidence interval [CI] 3.2 to 4.6). Eighty-two (66%) of the case-patients were male; 42 (34%) were female. The median age at death was 34.5 years (range 7–81 years). Most patients (107, 86.3%) were foreign-born, and 90 (72.6%) had emigrated from Mexico. Seventeen (13.7%) deaths occurred in U.S.-born residents. Cysticercosis death rates were higher in Latino residents of California (13.0/106) than in other racial/ethnic groups (0.4/106), in males (5.2/106) than in females (2.7/106), and in persons >14 years of age (5.0/106). Cysticercosis is a preventable cause of premature death, particularly among young Latino persons in California and may be a more common cause of death in the United States than previously recognized

Shaping Industrial Relations in a Digitalising Services Industry-Challenges and Opportunities for Social Partners. Service Markets Report.

status: publishe

A comparison of work environment, job insecurity, and health between marginal part-time workers and full-time workers in Denmark using pooled register data

OBJECTIVES: This study aimed to evaluate characteristics of the work environment, job insecurity, and health of marginal part‐time workers (8.0‐14.9 hours/week) compared with full‐time workers (32.0‐40.0 hours/week). METHODS: The study population included employees in the survey Work Environment and Health in Denmark (WEHD) in 2012, 2014, or 2016 (n = 34 960). Survey information from WEHD on work environment and health was linked with register‐based information of exposure based on working hours 3 months prior to the survey, obtained from the register Labour Market Account. Associations between marginal part‐time work and work environment and health were assessed using logistic regression models. RESULTS: Marginal part‐time workers reported less quantitative job demands, lower levels of influence at work, poorer support from colleagues and leaders, less job satisfaction and poorer safety, as well as more job insecurity. Results on negative social relations in the workplace and physical workload were more ambiguous. Marginal part‐time workers were more likely to report poorer self‐rated health, treatment‐requiring illness, and depressive symptoms compared with full‐time workers. Adjusting for characteristics of the work environment showed an indication of altered odds ratios for self‐rated health and depressive symptoms, whereas job insecurity did not. CONCLUSIONS: This study finds that marginal part‐time workers experience a poorer psychosocial work environment and safety, higher job insecurity, and poorer health than full‐time workers. Work environment characteristics may confound or mediate the association between marginal part‐time work and health. However, prospective studies are needed to determine the causal direction of the revealed associations

Unveiling the Ecological Applications of Ancient DNA From Mollusk Shells

The shells of marine mollusks represent promising metagenomic archives of the past, adding to bones, teeth, hairs, and environmental samples most commonly examined in ancient DNA research. Seminal work has established that DNA recovery from marine mollusk shells depends on their microstructure, preservation and disease state, and that authentic ancient DNA could be retrieved from specimens as old as 7,000 years. Here, we significantly push the temporal limit for shell DNA recovery to >= 100,000 years with the successful genetic characterization of one Portlandia arctica and one Mytilus mussel sample collected within a dated permafrost layer from the Taimyr Peninsula, Russia. We expand the analysis of ancient DNA in carbonate shells to a larger number of genera (Arctica, Cernuella, Crassostrea, Dreissena, Haliotis, Lymnaea, Margaritifera, Pecten, Ruditapes, Venerupis) from marine, freshwater and terrestrial environments. We demonstrate that DNA from ancient shells can provide sufficient resolution for taxonomic, phylogenetic and/or population assignment. Our results confirm mollusk shells as long-term DNA reservoirs, opening new avenues for the investigation of environmental changes, commercial species management, biological invasion, and extinction. This is especially timely in light of modern threats to biodiversity and ecosystems