O-GlcNAcylation dynamics in the brain

The role of post-translational modifications in the brain such as phosphorylationand ubiquitination have been well studied. However, the role of O-GlcNAcylation indistinct subpopulations of neurons remains unknown. This post-translationalmodification is an addition of single sugar moiety O-GlcNAc, derived from glucosemetabolism, to serine or threonine residue of proteins. O-GlcNAcylation is catalyzed byO-GlcNAc transferase (OGT), a highly expressed metabolic sensor enzyme in the brain,shown to be a gatekeeper for neuronal function and health. Here, we investigated the roleof OGT and O-GlcNAc dynamics in the brain. First, we demonstrated under the fastedstate, brain regions such as the paraventricular nucleus of hypothalamus, cortex andcerebellum, have significant reduction in O-GlcNAc levels. While the hippocampusregions, CA3 and dentate gyrus, have increased levels of O-GlcNAcylation. Then in orderto investigate the role of O-GlcNAcylation in Parvalbumin-positive inhibitoryinterneurons (PV), we generated a PV-specific-OGT knockout mouse line (PV.OGTKO).Our detailed behavioral and histological analysis indicated that loss of OGT in PVneurons leads to lower survival rates, motor defects, and loss of PV neurons. Overall, ourresults suggest the OGT plays crucial role in PV neuronal health and survival

O-GlcNAcylation dynamics in the brain

The role of post-translational modifications in the brain such as phosphorylationand ubiquitination have been well studied. However, the role of O-GlcNAcylation indistinct subpopulations of neurons remains unknown. This post-translationalmodification is an addition of single sugar moiety O-GlcNAc, derived from glucosemetabolism, to serine or threonine residue of proteins. O-GlcNAcylation is catalyzed byO-GlcNAc transferase (OGT), a highly expressed metabolic sensor enzyme in the brain,shown to be a gatekeeper for neuronal function and health. Here, we investigated the roleof OGT and O-GlcNAc dynamics in the brain. First, we demonstrated under the fastedstate, brain regions such as the paraventricular nucleus of hypothalamus, cortex andcerebellum, have significant reduction in O-GlcNAc levels. While the hippocampusregions, CA3 and dentate gyrus, have increased levels of O-GlcNAcylation. Then in orderto investigate the role of O-GlcNAcylation in Parvalbumin-positive inhibitoryinterneurons (PV), we generated a PV-specific-OGT knockout mouse line (PV.OGTKO).Our detailed behavioral and histological analysis indicated that loss of OGT in PVneurons leads to lower survival rates, motor defects, and loss of PV neurons. Overall, ourresults suggest the OGT plays crucial role in PV neuronal health and survival

Social and Cultural Euphemism in Saudi Arabic: a Semantic, a Pragmatic and a Sociolinguistic Analysis

This paper explores the universal linguistic phenomenon of the social and cultural euphemism in Saudi Arabic. It aims at improving the understanding of other cultures' readers of the Saudi culture, concerning uses of euphemism, and simultaneously showing how some linguistic expressions are essentially products of social and cultural pressures. To examine this notion, the study analyzes and classifies examples of the most frequently used Saudi Arabic euphemism, based on various topics. The study shows that the social and cultural factors are very influential in expressing euphemism. It also reveals a clear and a huge shift in the use of euphemism in the Saudi culture, where Saudis did not apply euphemisms frequently in the past, as they are applying these days. Because of the new development of the country’s economy, openness, interfaith dialogue, cultural communication, new lifestyles have emerged and called for more prestigious linguistic behavior. It is hoped that the study would uncover why there are certain sensitive situations where euphemism is needed, such as those of religion, social circumstances, and death situations.

Social and Cultural Euphemism in Saudi Arabic: a Semantic, a Pragmatic and a Sociolinguistic Analysis

This paper explores the universal linguistic phenomenon of the social and cultural euphemism in Saudi Arabic. It aims at improving the understanding of other cultures' readers of the Saudi culture, concerning uses of euphemism, and simultaneously showing how some linguistic expressions are essentially products of social and cultural pressures. To examine this notion, the study analyzes and classifies examples of the most frequently used Saudi Arabic euphemism, based on various topics. The study shows that the social and cultural factors are very influential in expressing euphemism. It also reveals a clear and a huge shift in the use of euphemism in the Saudi culture, where Saudis did not apply euphemisms frequently in the past, as they are applying these days. Because of the new development of the country’s economy, openness, interfaith dialogue, cultural communication, new lifestyles have emerged and called for more prestigious linguistic behavior. It is hoped that the study would uncover why there are certain sensitive situations where euphemism is needed, such as those of religion, social circumstances, and death situations

Large-scale map of RNA-binding protein interactomes across the mRNA life cycle

mRNAs interact with RNA-binding proteins (RBPs) throughout their processing and maturation. While efforts have assigned RBPs to RNA substrates, less exploration has leveraged protein-protein interactions (PPIs) to study proteins in mRNA life-cycle stages. We generated an RNA-aware, RBP-centric PPI map across the mRNA life cycle in human cells by immunopurification-mass spectrometry (IP-MS) of ∼100 endogenous RBPs with and without RNase, augmented by size exclusion chromatography-mass spectrometry (SEC-MS). We identify 8,742 known and 20,802 unreported interactions between 1,125 proteins and determine that 73% of the IP-MS-identified interactions are RNA regulated. Our interactome links many proteins, some with unknown functions, to specific mRNA life-cycle stages, with nearly half associated with multiple stages. We demonstrate the value of this resource by characterizing the splicing and export functions of enhancer of rudimentary homolog (ERH), and by showing that small nuclear ribonucleoprotein U5 subunit 200 (SNRNP200) interacts with stress granule proteins and binds cytoplasmic RNA differently during stress

Impaired mitophagy in Sanfilippo a mice causes hypertriglyceridemia and brown adipose tissue activation.

Lysosomal storage diseases result in various developmental and physiological complications, including cachexia. To study the causes for the negative energy balance associated with cachexia, we assessed the impact of sulfamidase deficiency and heparan sulfate storage on energy homeostasis and metabolism in a mouse model of type IIIa mucopolysaccharidosis (MPS IIIa, Sanfilippo A syndrome). At 12-weeks of age, MPS IIIa mice exhibited fasting and postprandial hypertriglyceridemia compared with wildtype mice, with a reduction of white and brown adipose tissues. Partitioning of dietary [3H]triolein showed a marked increase in intestinal uptake and secretion, whereas hepatic production and clearance of triglyceride-rich lipoproteins did not differ from wildtype controls. Uptake of dietary triolein was also elevated in brown adipose tissue (BAT), and notable increases in beige adipose tissue occurred, resulting in hyperthermia, hyperphagia, hyperdipsia, and increased energy expenditure. Furthermore, fasted MPS IIIa mice remained hyperthermic when subjected to low temperature but became cachexic and profoundly hypothermic when treated with a lipolytic inhibitor. We demonstrated that the reliance on increased lipid fueling of BAT was driven by a reduced ability to generate energy from stored lipids within the depot. These alterations arose from impaired autophagosome-lysosome fusion, resulting in increased mitochondria content in beige and BAT. Finally, we show that increased mitochondria content in BAT and postprandial dyslipidemia was partially reversed upon 5-week treatment with recombinant sulfamidase. We hypothesize that increased BAT activity and persistent increases in energy demand in MPS IIIa mice contribute to the negative energy balance observed in patients with MPS IIIa