Beyond Cell Penetrating Peptides: Designed Molecular Transporters

Inspired originally by peptides that traverse biological barriers, research on molecular transporters has since identified the key structural requirements that govern cellular entry, leading to new, significantly more effective and more readily available agents. These new drug delivery systems enable or enhance cellular and tissue uptake, can be targeted, and provide numerous additional advantages of significance in imaging, diagnostics and therapy.     

Pegylated TRAIL retains anti-leukemic cytotoxicity and exhibits improved signal transduction activity with respect to TRAIL

To improve the pharmacokinetic profile of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) an N-terminal specific pegylation was performed to generate pegylated TRAIL (PEG-TRAIL). In in vitro experiments, we found that although PEG-TRAIL was slightly less efficient than recombinant TRAIL in promoting leukemic cell apoptosis, it showed an improved ability to promote migration of bone-marrow mesenchymal stem cells and to elicit the ERK1/2 intracellular signal transduction pathway. Overall, these data suggest that TRAIL pegylation retains, or even enhances, the biological activities of TRAIL relevant for its therapeutic applications.     

Weight-related teasing,emotional eating,and weight control behaviors in Hispanic and African American girls

PurposeTo assess the association among parent and peer weight-related teasing, emotional eating, and weight control behaviors in minority girls.Methods141 Hispanic and African American preadolescent girls (mean age = 11.1 years, SD = 1.5 years) participated. Most of the participants were of Hispanic origin, had a bicultural orientation, and were obese. Participants completed surveys assessing weight-related teasing, emotional eating, weight control behaviors, demographic, and acculturation characteristics. Body weight and height were also assessed. Hierarchical regression analyses were run to determine the associations among study variables.ResultsFifty-nine percent of participants reported being weight-related teased by peers and 42% participants reported weight-related teasing by parents. Weight-related teasing by parent was associated with emotional eating and binge eating, whereas peer weight-related teasing was only associated with emotional eating.ConclusionsFindings demonstrated the differential association of weight-related teasing from peers and parents to emotional and binge eating in minority girls.     

“When Looking Back on My Past Life I Regret…”: Retrospective Regret in the Second Half of Life

ABSTRACT

The study investigated the frequency, themes, and attributions for significant regrets in a random probability sample of 3,917 German and Dutch nationals between the ages of 40 and 85 years. It was found that 14% did not have any regrets in spontaneous memory, and that this increased with the age of the respondents. With respect to mentioned regrets, older people, women, and those living in the former East Germany were more likely to recall externally attributed events; younger participants, men, West Germans, and the Dutch recalled more internally attributed events. Largely, memories related to 4 major themes: (a) mistakes, behavior, and bad decisions in general; (b) hard times; (c) social relationships; and (d) missed educational opportunities. The importance of these themes, however, varied according to age, gender, and regional belonging. Differences in the kind of attribution and in the centrality of themes are discussed in terms of lifespan theory, death preparation, and cultural differences.     

Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant

We used the muscle creatine kinase (MCK) conditional frataxin knockout mouse to elucidate how frataxin deficiency alters iron metabolism. This is of significance because frataxin deficiency leads to Friedreich''s ataxia, a disease marked by neurologic and cardiologic degeneration. Using cardiac tissues, we demonstrate that frataxin deficiency leads to down-regulation of key molecules involved in 3 mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase Nfs1), mitochondrial iron storage (mitochondrial ferritin), and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxidase, hydroxymethylbilane synthase, uroporphyrinogen III synthase, and ferrochelatase). This marked decrease in mitochondrial iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excessive mitochondrial iron observed. This effect is compounded by increased iron availability for mitochondrial uptake through (i) transferrin receptor1 up-regulation, increasing iron uptake from transferrin; (ii) decreased ferroportin1 expression, limiting iron export; (iii) increased expression of the heme catabolism enzyme heme oxygenase1 and down-regulation of ferritin-H and -L, both likely leading to increased “free iron” for mitochondrial uptake; and (iv) increased expression of the mammalian exocyst protein Sec15l1 and the mitochondrial iron importer mitoferrin-2 (Mfrn2), which facilitate cellular iron uptake and mitochondrial iron influx, respectively. Our results enable the construction of a model explaining the cytosolic iron deficiency and mitochondrial iron loading in the absence of frataxin, which is important for understanding the pathogenesis of Friedreich''s ataxia.     

Promyelocytic leukemia protein in mesenchymal stem cells is essential for leukemia progression

The dynamic interactions between leukemic cells and cells resident within the bone marrow microenvironment are vital for leukemia progression. The lack of detailed knowledge about the cellular and molecular mechanisms involved in this cross-talk restricts the design of effective treatments. Guarnerio et al. (2018) by using state-of-the-art techniques, including sophisticated Cre/loxP technologies in combination with leukemia mouse models, reveal that mesenchymal stem cells via promyelocytic leukemia protein (Pml) maintain leukemic cells in the bone marrow niche. Strikingly, genetic deletion of Pml in mesenchymal stem cells raised survival of leukemic mice under chemotherapeutic treatment. The emerging knowledge from this research provides a novel target in the bone marrow niche for therapeutic benefit in leukemia.