The LDL receptor-related protein-1 (LRP1) is highly expressed in numerous cell types, and its impairment is associated with obesity, diabetes, and fatty liver disease. However, the mechanisms linking LRP1 to metabolic disease are not completely understood. Here, we compared the metabolic phenotype of C57BL/6J wild type and LRP1 knock-in mice carrying an inactivating mutation in the distal NPxY motif after feeding a low fat (LF) diet or high fat diets with (HFHC) or without (HF) cholesterol supplementation. In response to HF feeding, both groups developed hyperglycemia, hyperinsulinemia, and hyperlipidemia, as well as increased adiposity with adipose tissue inflammation and liver steatosis. However, when animals were fed the HF diet supplemented with cholesterol, the LRP1 NPxY mutation prevents hypercholesterolemia, reduces adipose tissue and brain inflammation, and limits liver progression to steatohepatitis. Nevertheless, insulin signaling is impaired in LRP1 NPxY mutant hepatocytes and this mutation does not protect against HFHC-induced insulin resistance. The selective metabolic improvement observed in HFHC-fed LRP1 NPxY mutant mice is due to an apparent increase of hepatic LDL receptor levels, leading to an elevated rate of plasma lipoprotein clearance and lowering of plasma and hepatic cholesterol levels. The unique metabolic phenotypes displayed by LRP1 NPxY mutant mice in response to HF or HFHC diet feeding indicate an LRP1-cholesterol axis in modulating tissue inflammation. The LRP1 NPxY mutant mouse phenotype differs from phenotypes observed in mice with tissue-specific LRP1 inactivation, thus highlighting the importance of an integrative approach to evaluate how global LRP1 dysfunction contributes to metabolic disease development.

Deficiency of glucocerebrosidase (GBA), a lysosomal β-glucosidase, causes Gaucher disease. The enzyme hydrolyzes β-glucosidic substrates and transglucosylates cholesterol to cholesterol-β-glucoside. Here we show that recombinant human GBA also cleaves β-xylosides and transxylosylates cholesterol. The xylosyl-cholesterol formed acts as acceptor for subsequent formation of di-xylosyl-cholesterol. Common mutant forms of GBA from patients with Gaucher disease with reduced β-glucosidase activity were similarly impaired in β-xylosidase, transglucosidase and transxylosidase activities, except for a slightly reduced xylosidase/glucosidase activity ratio of N370S GBA and a slightly reduced transglucosylation/glucosidase activity ratio of D409H GBA. XylChol was found to be reduced in spleen from Gaucher disease patients. The origin of newly identified XylChol in mouse and human tissues was investigated. Cultured human cells exposed to exogenous β-xylosides generated XylChol in a manner dependent on active lysosomal GBA but not the cytosol-facing β-glucosidase GBA2. We later sought an endogenous β-xyloside acting as donor in transxylosylation reactions, identifying xylosylated ceramide (XylCer) in cells and tissues that serve as donor in the formation of XylChol. UDP-glucosylceramide synthase (GCS) was unable to synthesize XylChol but could catalyse formation of XylCer. Thus, food-derived β-D-xyloside and XylCer are potential donors for the GBA-mediated formation of XylChol in cells. The enzyme GCS produces XylCer at a low rate. Our findings point to further catalytic versatility of GBA and prompt a systematic exploration of the distribution and role of xylosylated lipids.

The acyltransferase LCAT mediates FA esterification of plasma cholesterol. In vitro studies have shown that LCAT also FA-esterifies several oxysterols, but in vivo evidence is lacking. Here, we measured both free and FA-esterified forms of sterols in 206 healthy volunteers and 8 individuals with genetic LCAT deficiency, including familial LCAT deficiency (FLD) and fish-eye disease (FED). In the healthy volunteers, the mean values of the ester-to-total molar ratios of the following sterols varied: 4β-hydroxycholesterol (4βHC), 0.38; 5,6α-epoxycholesterol (5,6αEC), 0.46; 5,6β-epoxycholesterol (5,6βEC), 0.51; cholesterol, 0.70; cholestane-3β,5α,6β-triol (CT), 0.70; 7-ketocholesterol (7KC), 0.75; 24S-hydroxycholesterol (24SHC), 0.80; 25-hydroxycholesterol (25HC), 0.81; 27-hydroxycholesterol (27HC), 0.86; and 7α-hydroxycholesterol (7αHC), 0.89. In the individuals with LCAT deficiency, the plasma levels of the FA-esterified forms of cholesterol, 5,6αEC, 5,6βEC, CT, 7αHC, 7KC, 24SHC, 25HC, and 27HC, were significantly lower than those in the healthy volunteers. The individuals with FLD had significantly lower FA-esterified forms of 7αHC, 24SHC, and 27HC than those with FED. It is of note that, even in the three FLD individuals with negligible plasma cholesteryl ester, substantial amounts of the FA-esterified forms of 4βHC, 5,6αEC, 7αHC, 7KC, and 27HC were present. We conclude that LCAT has a major role in the FA esterification of many plasma oxysterols but contributes little to the FA esterification of 4βHC. Substantial FA esterification of 4βHC, 5,6αEC, 7αHC, 7KC, and 27HC is independent of LCAT.

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3’s novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

Accompanied with nutrition transition, non-HDL-C levels of individuals in Asian countries has increased rapidly, which has caused the global epicenter of nonoptimal cholesterol to shift from Western countries to Asian countries. Thus, it is critical to underline major genetic and dietary determinants. In the current study of 2,330 Chinese individuals, genetic risk scores (GRSs) were calculated for total cholesterol (TC; GRS_TC, 57 SNPs), LDL-C (GRS_LDL-C, 45 SNPs), and HDL-C (GRS_HDL-C, 65 SNPs) based on SNPs from the Global Lipid Genetics Consortium study. Cholesterol intake was estimated by a 74-item food-frequency questionnaire. Associations of dietary cholesterol intake with plasma TC and LDL-C strengthened across quartiles of the GRS_TC (effect sizes: –0.29, 0.34, 2.45, and 6.47; P_interaction = 0.002) and GRS_LDL-C (effect sizes: –1.35, 0.17, 5.45, and 6.07; P_interaction = 0.001), respectively. Similar interactions with non-HDL-C were observed between dietary cholesterol and GRS_TC (P_interaction = 0.001) and GRS_LDL-C (P_interaction = 0.004). The adverse effects of GRS_TC on TC (effect sizes across dietary cholesterol quartiles: 0.51, 0.82, 1.21, and 1.31; P_interaction = 0.023) and GRS_LDL-C on LDL-C (effect sizes across dietary cholesterol quartiles: 0.66, 0.52, 1.12, and 1.56; P_interaction = 0.020) were more profound in those having higher cholesterol intake compared with those with lower intake. Our findings suggest significant interactions between genetic susceptibility and dietary cholesterol intake on plasma cholesterol profiles in a Chinese population.

Nonsmall cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. While mutations in Kras and overexpression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc combined with surface analysis lipid profiling of lung tumors and transcriptomics to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that the activation of Myc leads to the accumulation of cholesteryl esters (CEs) stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumors in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux, and accumulation of CE-rich lipid droplets in lung tumors. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.

The rise of drug-resistant tuberculosis poses a major risk to public health. Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. However, the underlying molecular mechanisms are unknown. In this study, we used an in vitro macrophage infection model to investigate simvastatin’s anti-tubercular activity by systematically inhibiting each branch of the mevalonate pathway and evaluating the effects of the branch-specific inhibitors on mycobacterial growth. The anti-tubercular activity of simvastatin used at clinically relevant doses specifically targeted the cholesterol biosynthetic branch rather than the prenylation branches of the mevalonate pathway. Using Western blot analysis and AMP/ATP measurements, we found that simvastatin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, the AMPK-mTORC1-TFEB axis, and Mycobacterium tuberculosis infection control, and uncover new anti-tubercular therapy targets.

Lipoproteins play a key role in transport of cholesterol to and from tissues. Recent studies have also demonstrated that red blood cells (RBCs), which carry large quantities of free cholesterol in their membrane, play an important role in reverse cholesterol transport. However, the exact role of RBCs in systemic cholesterol metabolism is poorly understood. RBCs were incubated with autologous plasma or isolated lipoproteins resulting in a significant net amount of cholesterol moved from RBCs to HDL, while cholesterol from LDL moved in the opposite direction. Furthermore, the bi-directional cholesterol transport between RBCs and plasma lipoproteins was saturable and temperature-, energy-, and time-dependent, consistent with an active process. We did not find LDLR, ABCG1, or scavenger receptor class B type 1 in RBCs but found a substantial amount of ABCA1 mRNA and protein. However, specific cholesterol efflux from RBCs to isolated apoA-I was negligible, and ABCA1 silencing with siRNA or inhibition with vanadate and Probucol did not inhibit the efflux to apoA-I, HDL, or plasma. Cholesterol efflux from and cholesterol uptake by RBCs from Abca1^+/+ and Abca1^–/– mice were similar, arguing against the role of ABCA1 in cholesterol flux between RBCs and lipoproteins. Bioinformatics analysis identified ABCA7, ABCG5, lipoprotein lipase, and mitochondrial translocator protein as possible candidates that may mediate the cholesterol flux. Together, these results suggest that RBCs actively participate in cholesterol transport in the blood, but the role of cholesterol transporters in RBCs remains uncertain.

War Time: Temporality and the Decline of Western Military Power Book dora.popova 22 February 2021

In War Time the Western way of war, its pace and timing, are discussed and analysed by experts who question the West’s ability to maintain its military superiority given the political and strategic failures of interventions in Iraq and Afghanistan.

In War Time, war studies experts examine the trajectory of Western military power. They discuss conflicting perceptions of time anchored within Western political and military institutions, and the Western attachment to fast-paced warfare at the expense of longer-term political solutions.

Divided into three sections, the book covers ‘civic militarism’ and the trajectory of Western power, Western perceptions of time and the international normative order, and military operations and temporality. War Time explains why the West has been overwhelmingly powerful on the battlefield and yet strategically and politically weak as exemplified by the return of the Taliban and the hasty evacuation of troops and personnel from Afghanistan.

The book identifies policies that decision-makers must adopt to stave off the decline of Western military dominance.

This book is part of the Insights series.

Watch the event

A special event was held in March 2021 to mark the launch of the book. View the event here.

Praise for War Time

About the editors

Sten Rynning is professor of war studies at the University of Southern Denmark.

Olivier Schmitt is professor with special responsibilities at the Center for War Studies, University of Southern Denmark, and currently director of research and studies at the French Institute for Higher National Defence Studies.

Amelie Theussen is assistant professor at the Center for War Studies, University of 
Southern Denmark.

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• Rest of world (via Brookings Institution Press)
• Students (via Browns Books)

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AMERICUS, Ga. — Georgia Southwestern State University graduate guard Destiny Garrett was named the Peach Belt Conference Women's Basketball Player of the Week this afternoon by the league office. Garrett set a school record with 13 assists in the 17th-ranked Lady Hurricanes 85-61 win over Florida Tech on Saturday and completed her first-ever double-double with a career-best 21 points. Garrett ...

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WILMINGTON, Del. – Delaware Governor John Carney, U.S. Senators Tom Carper and Chris Coons, and Congresswoman Lisa Blunt Rochester (all D-Del.) today announced that Delaware will receive $11,021,366 from the Centers for Disease Control and Prevention (CDC) to strengthen the First State’s public health workforce and infrastructure. Nationwide, the CDC is awarding $3.2 billion to […]

WILMINGTON, Del. – Today, Delaware Governor John Carney, U.S. Senators Tom Carper and Chris Coons and U.S. Representative Lisa Blunt Rochester (all D-Del.) announced $127.5 million for Port Wilmington as part of the U.S. Environmental Protection Agency’s (EPA) Clean Ports Program, a $3 billion investment by the Biden-Harris Administration in zero-emission port equipment and infrastructure. The […]

[DA] Note to editors: Please find attached soundbite by Ian Cameron MP.

Expert: Western Public Health Authorities’ Communication Missteps in Dealing with COVID Led to Public Mistrust Expert: Western Public Health Authorities’ Communication Missteps in Dealing with COVID Led to Public Mistrust

Hundreds of disgruntled women and youths from Zamfara State, on Tuesday, took their protest to the headquarters of the Department of Security Services in Abuja, over heightened insecurity in the state. The aggrieved persons blamed the immediate-past governor of the state and now Minister of State for Defence, Bello Matawalle, for the heightened activities of

THE HAGUE, Netherlands —  Police detained several people Sunday for taking part in a demonstration in central Amsterdam that had been outlawed following violence targeting fans of an Israeli soccer club, a local broadcaster reported.  Amsterdam Mayor Femke Halsema banned all demonstrations over the weekend in the aftermath of the grim scenes of youths on scooters and on foot attacking Maccabi Tel Aviv supporters on Thursday and Friday in what was widely condemned as a violent outburst of antisemitism in the Dutch capital.  Israel's ambassador to the Netherlands said that 2,000 Israelis were brought home on special flights from Amsterdam over the past few days  Before the match against Ajax, Maccabi fans also tore a Palestinian flag off a building in Amsterdam and chanted anti-Arab slogans on their way to the stadium. There were also reports of Maccabi fans starting fights.  Video on local broadcaster AT5 showed police detaining one man Sunday who was taking part in a small demonstration on the central Dam Square. The protesters yelled slogans including "Free, free Palestine." AT5 reported that about 20 people were detained.  Amsterdam Municipality said on X that police had begun arresting demonstrators who refused to leave the square, which is in the heart of the city's downtown shopping area and close to the historic canal network.  Organizers of the protest went to court on Sunday morning seeking an injunction to allow the demonstration, but a judge upheld the ban imposed by the municipality.  At the hearing, senior Amsterdam police officer Olivier Dutilh said that there were again incidents overnight targeting people thought to be Jewish, including some being ordered out of taxis and others being asked to produce their passports to confirm their nationality.  Police launched a large-scale investigation Friday after gangs of youths conducted what Amsterdam's mayor called "hit and run" attacks on fans that were apparently inspired by calls on social media to target Jewish people. Five people were treated at hospitals and more than 60 suspects were arrested.  Israeli Foreign Minister Gideon Saar rushed to the Netherlands on Friday and offered Israel's help in the police investigation. He met on Saturday with Dutch Prime Minister Dick Schoof and said in a statement that the attacks and demands to show passports "were reminiscent of dark periods in history." 

Dutch coach, Eric Ten Hag was eventually booted out of Manchester United 30 months after his appointment in May 2022. The former Ajax gaffer didn’t quite succeed with the Red Devils in terms of quality, squad depth and results but he was able to deliver two trophies( Carabao, FA Cup) in his two years in […]

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Huge crowds of antigovernment protesters Saturday encircled the Serbian state television building in downtown Belgrade to press their demand for autocratic President Aleksandar Vucic to ease his tight grip on the mainstream media and allow alternative voices. Tens of thousands of opposition supporters, some chanting slogans urging Vucic's resignation, streamed into the rain-drenched streets a day after the president's followers staged an equally big rally in the capital. Most of his supporters were bused into the capital from all over Serbia and some neighboring states. Outside the RTS TV headquarters, the crowds blew whistles and booed loudly. They say that according to the laws, state TV should be unbiased as a public broadcaster, but that it has been openly pro-government. Held for the fourth time since the early May shootings, the opposition-led protests appear to be shaping up into the biggest revolt against Vucic's autocratic rule during his over 10 years in power. The rallies initially erupted in response to two back-to-back mass shootings earlier this month that left 18 people dead and 20 wounded, many of them children from an elementary school. Other protest demands include the resignations of top officials and the revoking of licenses for pro-government media that air violent content and host crime figures and war criminals. Vucic has accused the opposition of abusing the shooting tragedy for political ends. Earlier Saturday, he stepped down from the helm of his populist party amid plans to form a wider political movement. Vucic named his close ally, Milos Vucevic, the current defense minister, as his successor. Holding umbrellas amid heavy rain Saturday, the protesters walked slowly around the RTS television building in central Belgrade, completely covering the streets in the entire area. Many held flowers in memory of the slain children and wore badges reading "vulture" or "hyena," mocking the expressions that officials used to describe the protesters. Vucic has said the new, national movement will be formed in June to include other parties, experts and prominent individuals and promote unity. Analysts say it is a bid to regroup amid mounting public pressure. Critics say the movement could lead to single-party rule, more or less as the case in Vladimir Putin's Russia, which Vucic supports. During the rally Friday, Vucic offered dialogue as he seeks ways to ease mounting public pressure. Opposition parties have pledged to press on with the demonstrations until their demands are fulfilled. They include the ouster of the interior minister and the intelligence chief; the revocation of nationwide broadcast licenses for two pro-government TV stations; and the dismissal of a media-monitoring body. "If they don't fulfill (the demands) we are not leaving from here," said Milica Tomic, a Belgrade resident. "We will be here, if it need be, every day, every week, whenever."

Heed this warning: Islamic fundamentalists may start with the Jews, but they won’t stop there.

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