Niemann-Pick disease type C (NPC) disease is a lipid-storage disorder that is caused by mutations in the genes encoding NPC proteins and results in lysosomal cholesterol accumulation. 2-Hydroxypropyl-β-cyclodextrin (CD) has been shown to reduce lysosomal cholesterol levels and enhance sterol homeostatic responses, but CD’s mechanism of action remains unknown. Recent work provides evidence that CD stimulates lysosomal exocytosis, raising the possibility that lysosomal cholesterol is released in exosomes. However, therapeutic concentrations of CD do not alter total cellular cholesterol, and cholesterol homeostatic responses at the ER are most consistent with increased ER membrane cholesterol. To address these disparate findings, here we used stable isotope labeling to track the movement of lipoprotein cholesterol cargo in response to CD in NPC1-deficient U2OS cells. Although released cholesterol was detectable, it was not associated with extracellular vesicles. Rather, we demonstrate that lysosomal cholesterol trafficks to the plasma membrane (PM), where it exchanges with lipoprotein-bound cholesterol in a CD-dependent manner. We found that in the absence of suitable extracellular cholesterol acceptors, cholesterol exchange is abrogated, cholesterol accumulates in the PM, and reesterification at the ER is increased. These results support a model in which CD promotes intracellular redistribution of lysosomal cholesterol, but not cholesterol exocytosis or efflux, during the restoration of cholesterol homeostatic responses.

Compared with humans, rodents have higher synthesis of cholesterol and bile acids (BAs) and faster clearance and lower levels of serum LDL-cholesterol. Paradoxically, they increase BA synthesis in response to bile duct ligation (BDL). Another difference is the production of hydrophilic 6-hydroxylated muricholic acids (MCAs), which may antagonize the activation of FXRs, in rodents versus humans. We hypothesized that the presence of MCAs is key for many of these metabolic differences between mice and humans. We thus studied the effects of genetic deletion of the Cyp2c70 gene, previously proposed to control MCA formation. Compared with WT animals, KO mice created using the CRISPR/Cas9 system completely lacked MCAs, and displayed >50% reductions in BA and cholesterol synthesis and hepatic LDL receptors, leading to a marked increase in serum LDL-cholesterol. The doubling of BA synthesis following BDL in WT animals was abolished in KO mice, despite extinguished intestinal fibroblast growth factor (Fgf)15 expression in both groups. Accumulation of cholesterol-enriched particles ("Lp-X") in serum was almost eliminated in KO mice. Livers of KO mice were increased 18% in weight, and serum markers of liver function indicated liver damage. The human-like phenotype of BA metabolism in KO mice could not be fully explained by the activation of FXR-mediated changes. In conclusion, the presence of MCAs is critical for many of the known metabolic differences between mice and humans. The Cyp2c70-KO mouse should be useful in studies exploring potential therapeutic targets for human disease.

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (^–/–) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.­

Fatty liver involves ectopic lipid accumulation and dysregulated hepatic oxidative metabolism, which can progress to a state of elevated inflammation and fibrosis referred to as nonalcoholic steatohepatitis (NASH). The factors that control progression from simple steatosis to NASH are not fully known. Here, we tested the hypothesis that dietary vitamin E (VitE) supplementation would prevent NASH progression and associated metabolic alterations induced by a Western diet (WD). Hyperphagic melanocortin-4 receptor-deficient (MC4R^–/–) mice were fed chow, chow+VitE, WD, or WD+VitE starting at 8 or 20 weeks of age. All groups exhibited extensive hepatic steatosis by the end of the study (28 weeks of age). WD feeding exacerbated liver disease severity without inducing proportional changes in liver triglycerides. Eight weeks of WD accelerated liver pyruvate cycling, and 20 weeks of WD extensively upregulated liver glucose and oxidative metabolism assessed by ²H/¹³C flux analysis. VitE supplementation failed to reduce the histological features of NASH. Rather, WD+VitE increased the abundance and saturation of liver ceramides and accelerated metabolic flux dysregulation compared with 8 weeks of WD alone. In summary, VitE did not limit NASH pathogenesis in genetically obese mice, but instead increased some indicators of metabolic dysfunction.

Cellular membranes are not homogenous mixtures of proteins; rather, they are segregated into microdomains on the basis of preferential association between specific lipids and proteins. These microdomains, called lipid rafts, are well known for their role in receptor signaling on the plasma membrane (PM) and are essential to such cellular functions as signal transduction and spatial organization of the PM. A number of disease states, including atherosclerosis and other cardiovascular disorders, may be caused by dysfunctional maintenance of lipid rafts. Lipid rafts do not occur only in the PM but also have been found in intracellular membranes and extracellular vesicles (EVs). Here, we focus on discussing newly discovered functions of lipid rafts and microdomains in intracellular membranes, including lipid and protein trafficking from the ER, Golgi bodies, and endosomes to the PM, and we examine lipid raft involvement in the production and composition of EVs. Because lipid rafts are small and transient, visualization remains challenging. Future work with advanced techniques will continue to expand our knowledge about the roles of lipid rafts in cellular functioning.

Lipid rafts are highly ordered regions of the plasma membrane that are enriched in cholesterol and sphingolipids and play important roles in many cells. In hematopoietic stem and progenitor cells (HSPCs), lipid rafts house receptors critical for normal hematopoiesis. Lipid rafts also can bind and sequester kinases that induce negative feedback pathways to limit proliferative cytokine receptor cycling back to the cell membrane. Modulation of lipid rafts occurs through an array of mechanisms, with optimal cholesterol efflux one of the major regulators. As such, cholesterol homeostasis also regulates hematopoiesis. Increased lipid raft content, which occurs in response to changes in cholesterol efflux in the membrane, can result in prolonged receptor occupancy in the cell membrane and enhanced signaling. In addition, certain diseases, like diabetes, may contribute to lipid raft formation and affect cholesterol retention in rafts. In this review, we explore the role of lipid raft-related mechanisms in hematopoiesis and CVD (specifically, atherosclerosis) and discuss how defective cholesterol efflux pathways in HSPCs contribute to expansion of lipid rafts, thereby promoting myelopoiesis and thrombopoiesis. We also discuss the utility of cholesterol acceptors in contributing to lipid raft regulation and disruption, and highlight the potential to manipulate these pathways for therapeutic gain in CVD as well as other disorders with aberrant hematopoiesis.

Chronic low-grade inflammation plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). In order to investigate the ability of different inflammatory blood cell parameters in predicting the development of GDM and pregnancy outcomes, 258 women with GDM and 1154 women without were included in this retrospective study. First-trimester neutrophil count outperformed white blood cell (WBC) count, and neutrophil-to-lymphocyte ratio (NLR) in the predictability for GDM. Subjects were grouped based on tertiles of neutrophil count during their first-trimester pregnancy. The results showed that as the neutrophil count increased, there was a step-wise increase in GDM incidence, as well as glucose and glycosylated hemoglobin (HbA1c) level, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), macrosomia incidence and newborn weight. Neutrophil count was positively associated with pre-pregnancy Body Mass Index (BMI), HOMA-IR and newborn weight. Additionally, neutrophil count was an independent risk factor for the development of GDM, regardless of the history of GDM. Spline regression showed that there was a significant linear association between GDM incidence and continuous neutrophil count when it exceeded 5.0 x 10⁹/L. This work suggested that first-trimester neutrophil count is closely associated with the development of GDM and adverse pregnancy outcomes.

Infants born to mothers with obesity have a greater risk for childhood obesity and metabolic diseases; however, the underlying biological mechanisms remain poorly understood. We used a Japanese macaque model to investigate whether maternal obesity combined with a western-style diet (WSD) impairs offspring muscle insulin action. Adult females were fed a control or WSD prior to and during pregnancy through lactation, and offspring subsequently weaned to a control or WSD. Muscle glucose uptake and signaling were measured ex vivo in fetal (n=5-8/group) and juvenile offspring (n=8/group). In vivo signaling was evaluated after an insulin bolus just prior to weaning (n=4-5/group). Maternal WSD reduced insulin-stimulated glucose uptake and impaired insulin signaling at the level of Akt phosphorylation in fetal muscle. In juvenile offspring, insulin-stimulated glucose uptake was similarly reduced by both maternal and post-weaning WSD and corresponded to modest reductions in insulin-stimulated Akt phosphorylation relative to controls. We conclude that maternal WSD leads to a persistent decrease in offspring muscle insulin-stimulated glucose uptake even in the absence of increased offspring adiposity or markers of systemic insulin resistance. Switching offspring to a healthy diet did not reverse the effects of maternal WSD on muscle insulin action suggesting earlier interventions may be warranted.

Elisabeth F.C. van Rossum
Oct 1, 2002; 51:3128-3134
Genetics

VOLUME 295 (2020) PAGES 4079–4092There was an error in the abstract. “The pyridinium cation hampers uptake of OPs into the central nervous system (CNS)” should read as “The pyridinium cation hampers uptake into the central nervous system (CNS).”

Western Bureau: A number of swimming officials in western Jamaica say that the region’s struggles with underdevelopment will continue even if the COVID-19 pandemic is brought under control. They say this is because they still lack proper pools to...

With thousands more migrants potentially traveling through the Western Balkans this year, this MPI Europe webinar explores the implications of the buttressed EU border on the bloc’s neighbors, including the issues of outsourcing migration control, EU support for addressing irregular migration in neighboring countries, and considerations for EU policymakers.

With thousands migrants potentially traveling through the Western Balkans this year, this MPI Europe webinar explores the implications of the buttressed EU border on the bloc’s neighbors, the migrants transiting these routes, and the local communities. Experts also explored how the European Union can support efforts to address irregular migration in neighboring countries, and what are the tradeoffs and considerations that policymakers must weigh. 

I’ve been talking to a man, we have mutual interest in each other. We talked on the phone for over an hour the night before last and it was an amazing conversation. The next day he had no contact with me, which in my mind it didn’t bother me and still kind of isn’t I think he just is doing his own thing and likes his personal space. I’m not too bothered or worried but still questioning why? Is it normal for a man to kinda disappear and have no contact for a day?

The two Upstate New York districts are venturing beyond the largely white region to tap a more diverse pool of educators.

Lester coached at Maryland from 1969-71. He was 96.

Roy Lester, who sandwiched a disappointing three-year stint as Maryland's football coach between a highly successful career at the high school level, has died. Lester's daughter, Amy Lester Greco, said on a Facebook post that her father died Sunday in Rockville, Maryland, due to complications from the new coronavirus. Lester made a name for himself in Maryland during a 10-year run at Richard Montgomery High School in Rockville during which the Rockets went unbeaten six times and had an 86-10-1 record.

"We investigate the potential of using high-resolution seismic methods for rock characterization and for targeting of gold deposits at the St. Ives gold camp. The application of seismic methods in hard-rock environments is challenged by complex structures, intrinsically low signal-to-noise ratio, regolith distortions, and access restrictions. If these issues can be addressed, then the unparalleled resolving power of reflection seismic can be used for mineral exploration. Appropriate spatial sampling of the wavefield combined with a survey geometry design and rigorous data processing to incorporate high fold and long offsets are necessary for creation of high-quality seismic images. In the hard-rock environment of Western Australia, accurate static corrections and multiphase velocity analysis are essential processing steps. This is followed by a rigorous quality control following each processing step. In such a case, we show that the role of reflection seismic could be lifted from mere identification of first-order structures to refined lithological analyses. Five deep boreholes with sonic logs and core sample test data wer eused to calibrate 2D seismic images. Despite seismic images were produced with relatively robust scaling it was possible to achieve reasonably high seismic-log correlation across three of the tightly spaced boreholes using a single composite wavelet. Amplitude-versus-offset (AVO) analysis indicated that gold-bearing structures may be related to elevated AVO effect and increased reflectivity. Consequently, partial stack analysis and acoustic and elastic inversions were conducted. These results and impedance crossplots were then evaluated against known gold occurrences. While still in the preliminary stages, hard-rock seismic imaging, inversion, and the application of AVO techniques indicated significant potential for targeting mineral reserves" -- Summary.

Peace (Philosophy)

London : Macmillan, 1878.

Berlin : Hirschwald, 1886.

[Rome?]

The California landmark is closed, but you can explore its bizarre architectural features from afar

The Kent State shootings further widened the chasm among a citizenry divided over the Vietnam War

It's been more than a week since there were any new or active cases of COVID-19 in the catchment area for the Northwestern Health Unit (NWHU), and staff can not focus increasing testing.

Hope you didn't pack away those winter boots yet: southwestern Manitoba, from Riding Mountain south to the Canada-U.S. border, is expected to get heavy rain and snow Friday night.

We can expect to see more seasonable temperatures by next weekend, says a meteorologist from Environment Canada.

Schools in western Quebec are getting ready to welcome students back next week, but things will look a lot different — and classrooms will likely be far from full. 

Villagers placed the bodies of three victims of a deadly gas leak from an LG Polymers plant in southern India at the gates of the site on Saturday and demanded the factory be shut down immediately and its top management arrested.

The bonspiel took place in Edmonton March 11-14, starting the same day COVID-19 was declared a global pandemic.

Penn State is implementing a new opt-in grading system for the spring 2020 semester that will give students flexibility, help preserve GPAs and minimize impacts to students’ transcripts during the academic challenges presented by the novel coronavirus public health crisis.

A former student of OM Panama brings the world to her small church in western Panama.

IRAQ’S prime ministerial merry-go-round continues to spin apace. Spy chief Mustafa al-Kadhimi, director of the country’s National Intelligence Service, is now the third prime minister designate this year, following the withdrawal of the two previous prospective candidates.

The National Labor Relations Board unanimously declined jurisdiction Monday in the case involving Northwestern University football players attempting to unionize.

Male circumcision reduces risk of HIV acquisition in men by 60% and is associated with other health benefits. Compared with adult circumcision, infant male circumcision is safer, less expensive, and represents a cost-saving intervention for HIV prevention in many settings.

IMC is little known in East Africa and is not routinely practiced. This is the first study to assess acceptability and uptake of IMC in East Africa among parents who were actually offered the procedure. (Read the full article)

Prenatal and postnatal organophosphate (cholinesterase inhibitor) pesticide exposure has been associated with delays in attention, memory, intelligence, and inhibitory control. Two recent studies reported decreased attention and working memory with greater exposure to organophosphates in boys but not in girls.

This is the first study to report associations between decreased acetylcholinesterase activity, a stable marker of cholinesterase inhibitor pesticide exposure, and lower overall neurodevelopment, attention, inhibitory control, and memory. These associations were present in boys but not in girls. (Read the full article)

Pennsylvania College of Technology’s National Sustainable Structures Center is adding a training site in Westmoreland County to enhance delivery of building science and energy efficiency training for the U.S. Department of Energy’s Weatherization Assistance Program.

BACKGROUND:

Elevated non–high-density lipoprotein cholesterol (HDL-C) levels are used to identify children at increased cardiovascular risk, but the use of non–HDL-C in childhood to predict atherosclerosis is unclear. We examined whether the National Heart, Lung, and Blood Institute classification of youth non–HDL-C status predicts high common carotid artery intima-media thickness in adulthood.

A first-leg comeback has put Manchester City in the driving seat as Real Madrid travel to north-west England facing a 2-1 deficit.

Gauteng, the Western Cape and KwaZulu-Natal are the hot spots for card fraud in South Africa, according to a report on global fraud activity.