Anja Jaeschke
Dec 9, 2020; 0:jlr.RA120001141v1-jlr.RA120001141
Research Articles

Ying Zou
Dec 1, 2020; 61:1589-1604
Research Articles

Amanda D.V. MacCannell
Nov 18, 2020; 0:jlr.ILR120001204v1-jlr.ILR120001204
Images in Lipid Research

If the OBSMARGINS= or OM= option is specified in an LSMEANS, LSMESTIMATE, or SLICE statement and a user-defined format is applied to any of the effect variables in the OM-data-set , PROC PLM incorrectly stops proce

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.

Genome-wide association studies (GWAS) have implicated ~380 genetic loci for plasma lipid regulation. However, these loci only explain 17-27% of the trait variance and a comprehensive understanding of the molecular mechanisms has not been achieved. In this study, we utilized an integrative genomics approach leveraging diverse genomic data from human populations to investigate whether genetic variants associated with various plasma lipid traits, namely total cholesterol (TC), high and low density lipoprotein cholesterol (HDL and LDL), and triglycerides (TG), from GWAS were concentrated on specific parts of tissue-specific gene regulatory networks. In addition to the expected lipid metabolism pathways, gene subnetworks involved in ‘interferon signaling’, ‘autoimmune/immune activation’, ‘visual transduction’, and ‘protein catabolism’ were significantly associated with all lipid traits. Additionally, we detected trait-specific subnetworks, including cadherin-associated subnetworks for LDL, glutathione metabolism for HDL, valine, leucine and isoleucine biosynthesis for TC, and insulin signaling and complement pathways for TG. Finally, utilizing gene-gene relations revealed by tissue-specific gene regulatory networks, we detected both known (e.g. APOH, APOA4, and ABCA1) and novel (e.g. F2 in adipose tissue) key regulator genes in these lipid-associated subnetworks. Knockdown of the F2 gene (Coagulation Factor II, Thrombin) in 3T3-L1 and C3H10T1/2 adipocytes reduced gene expression of Abcb11, Apoa5, Apof, Fabp1, Lipc, and Cd36, reduced intracellular adipocyte lipid content, and increased extracellular lipid content, supporting a link between adipose thrombin and lipid regulation. Our results shed light on the complex mechanisms underlying lipid metabolism and highlight potential novel targets for lipid regulation and lipid-associated diseases.

Bile acids (BAs) have been established as ubiquitous regulatory molecules implicated in a large variety of healthy and pathological processes. However, the scope of BA heterogeneity is often underrepresented in current literature. This is due in part to inadequate detection methods, which fail to distinguish the individual constituents of the BA pool. Thus, the primary aim of this study was to develop a method that would allow the simultaneous analysis of specific C24 BA species, and to apply that method to biological systems of interest. Herein, we describe the generation and validation of an LC-MS/MS assay for quantification of numerous BAs in a variety of cell systems and relevant biofluids and tissue. These studies included the first baseline level assessment for planar BAs, including allocholic acid, in cell lines, biofluids, and tissue in a nonhuman primate (NHP) laboratory animal, Macaca mulatta, in healthy conditions. These results indicate that immortalized cell lines make poor models for the study of BA synthesis and metabolism, whereas human primary hepatocytes represent a promising alternative model system. We also characterized the BA pool of M. mulatta in detail. Our results support the use of NHP models for the study of BA metabolism and pathology in lieu of murine models. Moreover, the method developed here can be applied to the study of common and planar C24 BA species in other systems.

Adaptive thermogenesis is highly dependent on uncoupling protein 1 (UCP1), a protein expressed by thermogenic adipocytes present in brown adipose tissue (BAT) and white adipose tissue (WAT). Thermogenic capacity of human and mouse BAT can be measured by positron emission tomography-computed tomography quantifying the uptake of ¹⁸F-fluodeoxyglucose or lipid tracers. BAT activation is typically studied in response to cold exposure or treatment with β-3-adrenergic receptor agonists such as CL316,243 (CL). Currently, it is unknown whether cold-stimulated uptake of glucose or lipid tracers is a good surrogate marker of UCP1-mediated thermogenesis. In metabolic studies using radiolabeled tracers, we found that glucose uptake is increased in mildly cold-activated BAT of Ucp1^–/– versus WT mice kept at subthermoneutral temperature. Conversely, lower glucose disposal was detected after full thermogenic activation achieved by sustained cold exposure or CL treatment. In contrast, uptake of lipoprotein-derived fatty acids into chronically activated thermogenic adipose tissues was substantially increased in UCP1-deficient mice. This effect is linked to higher sympathetic tone in adipose tissues of Ucp1^–/– mice, as indicated by elevated levels of thermogenic genes in BAT and WAT. Thus, glucose and lipoprotein handling does not necessarily reflect UCP1-dependent thermogenic activity, but especially lipid uptake rather mirrors sympathetic activation of adipose tissues.

Beiging of white adipose tissue (WAT) has beneficial effects on metabolism. Although it is known that beige adipocytes are active in lipid catabolism and thermogenesis, how they are regulated deserves more explorations. In this study, we demonstrate that stearoyl-CoA desaturase 1 (SCD1) in subcutaneous WAT (scWAT) responded to cold stimulation and was able to promote mobilization of triacylglycerol [TAG (triglyceride)]. In vitro studies showed that SCD1 promoted lipolysis in C3H10T1/2 white adipocytes. The lipolytic effect was contributed by one of SCD1’s products, oleic acid (OA). OA upregulated adipose TAG lipase and hormone-sensitive lipase expression. When SCD1 was overexpressed in the scWAT of mice, lipolysis was enhanced, and oxygen consumption and heat generation were increased. These effects were also demonstrated by the SCD1 knockdown experiments in mice. In conclusion, our study suggests that SCD1, known as an enzyme for lipid synthesis, plays a role in upregulating lipid mobilization through its desaturation product, OA.

The complexity and dynamics of the immensely heterogeneous glycoproteome of the prostate cancer (PCa) tumour micro-environment remain incompletely mapped, a knowledge gap that impedes our molecular-level understanding of the disease. To this end, we have used sensitive glycomics and glycoproteomics to map the protein-, cell- and tumour grade-specific N- and O-glycosylation in surgically-removed PCa tissues spanning five histological grades (n = 10/grade) and tissues from patients with benign prostatic hyperplasia (n = 5). Quantitative glycomics revealed PCa grade-specific alterations of the oligomannosidic-, paucimannosidic- and branched sialylated complex-type N-glycans, and dynamic remodelling of the sialylated core 1- and core 2-type O-glycome. Deep quantitative glycoproteomics identified ~7,400 unique N-glycopeptides from 500 N-glycoproteins and ~500 unique O-glycopeptides from nearly 200 O-glycoproteins. With reference to a recent Tissue and Blood Atlas, our data indicate that paucimannosidic glycans of the PCa tissues arise mainly from immune cell-derived glycoproteins. Further, the grade-specific PCa glycosylation arises primarily from dynamics in the cellular makeup of the PCa tumour microenvironment across grades involving increased oligomannosylation of prostate-derived glycoproteins and decreased bisecting GlcNAcylation of N-glycans carried by the extracellular matrix proteins. Further, elevated expression of several oligosaccharyltransferase subunits and enhanced N-glycoprotein site occupancy were observed associated with PCa progression. Finally, correlations between the protein-specific glycosylation and PCa progression were observed including increased site-specific core 2-type O-glycosylation of collagen VI. In conclusion, integrated glycomics and glycoproteomics have enabled new insight into the complexity and dynamics of the tissue glycoproteome associated with PCa progression generating an important resource to explore the underpinning disease mechanisms.

The early detection of pancreatic ductal adenocarcinoma is a complex clinical obstacle yet is key to improving the overall likelihood of patient survival. Current and prospective carbohydrate biomarkers CA19-9 and sTRA are sufficient for surveilling disease progression yet are not approved for delineating PDAC from other abdominal cancers and non-cancerous pancreatic pathologies. To further understand these glycan epitopes, an imaging mass spectrometry approach was utilized to assess the N-glycome of the human pancreas and pancreatic cancer in a cohort of PDAC patients represented by tissue microarrays and whole tissue sections. Orthogonally, these same tissues were characterized by multi-round immunofluorescence which defined expression of CA19-9 and sTRA as well as other lectins towards carbohydrate epitopes with the potential to improve PDAC diagnosis. These analyses revealed distinct differences not only in N-glycan spatial localization across both healthy and diseased tissues but importantly between different biomarker-categorized tissue samples. Unique sulfated bi-antennary N-glycans were detected specifically in normal pancreatic islets. N-glycans from CA19-9 expressing tissues tended to be bi-, tri- and tetra-antennary structures with both core and terminal fucose residues and bisecting N-acetylglucosamines. These N-glycans were detected in less abundance in sTRA-expressing tumor tissues, which favored tri- and tetra-antennary structures with polylactosamine extensions. Increased sialylation of N-glycans was detected in all tumor tissues. A candidate new biomarker derived from IMS was further explored by fluorescence staining with selected lectins on the same tissues. The lectins confirmed the expression of the epitopes in cancer cells and revealed different tumor-associated staining patterns between glycans with bisecting GlcNAc and those with terminal GlcNAc. Thus, the combination of lectin-IHC and IMS techniques produces more complete information for tumor classification than the individual analyses alone. These findings potentiate the development of early assessment technologies to rapidly and specifically identify PDAC in the clinic that may directly impact patient outcomes.

Exploring Public International Law Issues with Chinese Scholars – Part Four Other resource sysadmin 30 October 2018

As part of a roundtable series, Chatham House and the China University of Political Science and Law (CUPL) held a two-day roundtable in Beijing on emerging issues of public international law.

The specific objectives were to:

• create a platform for Chinese international law academics working on international human rights law issues to present their thinking and exchange ideas with counterparts from outside China;
• build stronger understanding within the wider international law community of intellectual debates taking place in China about the international human rights system and China’s role within it;
• support networking between Chinese and non-Chinese academics working on international human rights and related areas of international law.

The roundtable forms part of a wider Chatham House project exploring China’s impact on the international human rights system and was inspired by early discussions with a burgeoning community of Chinese academics thinking, writing (mainly in Chinese) and teaching about international human rights law.

For CUPL, one of the largest and most prestigious law schools in China and perhaps the only university in the world with an entire faculty of international law, the initiative is part of a drive to forge partnerships beyond China in the international law field.

The meeting was co-hosted with CUPL and involved 28 participants, consisting of 19 Chinese participants (from six leading research institutions in Beijing and Shanghai) and nine nonChinese participants (from eight leading research institutions in Australia, the Netherlands, the UK, Switzerland, Canada and Singapore).

To ensure continuity while also expanding the expert network being built, the fifth meeting included a mix of participants from the previous meetings and some new participants.

All discussions were held in English under the Chatham House Rule.

Issues to watch in 2023 The World Today mhiggins.drupal 29 November 2022

From nuclear proliferation to African debt, here are the issues six of our expert contributors expect to make the news in the year ahead.

Europe’s energy outlook

Mike Bradshaw, Professor of Global Energy, Warwick Business School

There is cautious optimism that Europe will endure this winter without an energy crisis. Gas prices have fallen, storage is 95 per cent full, and the autumn was mild. High summer gas prices cut industrial demand but domestic heating demand will be critical over the winter. Already, France’s problematic nuclear fleet and lower hydroelectric output mean Europe is using more gas to generate power. 

Russian pipeline gas supply to southern Europe has fallen by 55 per cent. While Asian demand has fallen, Europe has still paid record prices to secure additional liquefied natural gas (LNG), largely from America but also Russia. European demand for LNG this winter will push prices up, and these will rise even higher if China relaxes its Zero-Covid policy and demand recovers. However, with luck, Europe will avoid power cuts in early 2023. The problem is next winter. With less Russian pipeline gas and a tight LNG market, 90 per cent winter gas storage levels will be much harder to achieve. 

NATO’s resurgence

Alice Billon-Galland, Research Fellow, Europe Programme, Chatham House and one of 14 NATO Young Leaders

In response to Russia’s invasion of Ukraine, NATO adopted a new strategic concept. Member states will reinforce NATO battlegroups and bolster higher readiness forces from 40,000 troops to more than 300,000, while striving to avoid escalation with Russia. Turkey’s attempts to block Sweden and Finland’s NATO membership will preoccupy Jens Stoltenberg, the Secretary-General, until he leaves his post next autumn.

Expect arguments on defence spending in the run-up to the July summit in Vilnius. Although only nine of its 30 members are expected to meet the 2 per cent spending target, the debate is moving towards 3 per cent, in part to reduce dependency on American assets and hedge against the uncertainty of the 2024 US presidential election. Infrastructure vulnerabilities, such as the Nord Stream pipeline sabotage in the Baltic, will also be a focus. Otherwise, NATO ’s eyes will be on China: from its relations with Russia to the threat of cyberattacks.

Universal health reforms

Robert Yates, Executive Director, Centre for Universal Health, Chatham House

In response to the perma-crisis experienced by many populations this past year, some leaders are launching or extending universal health reforms. New left-wing leaders in Chile, Colombia and Brazil have promised to rebuild their publicly financed universal health systems. In Brazil, newly elected president Lula da Silva has pledged to increase public health spending and improve access to medicines. It is hoped Malaysia’s new coalition will carry forward its predecessor’s pledge to raise health spending to 5 per cent of GDP by 2027 to provide a universal package of free health services.

In September, world leaders will discuss universal health coverage at the UN General Assembly. There, Chatham House will publish its Commission for Universal Health report, identifying countries in which crises may trigger new national health programmes. Might this be when a US presidential candidate announces a platform to create a publicly financed health system?

Weapons of mass destruction

Patricia Lewis, Director of the International Security Programme, Chatham House

Since its illegal invasion of Ukraine, Russia has attacked civil nuclear power stations, falsely accused Ukraine of possessing bioweapons and radiological bombs, and threatened to use nuclear weapons. In contrast, NATO has instead demonstrated that deterrence can be highly effective with conventional weaponry. In the coming year, the Kremlin’s nuclear brinkmanship will still be a focus. Washington will try to restart bilateral nuclear negotiations with Moscow and similarly try to engage Beijing.

Following the failure of the nuclear Non-Proliferation Treaty Review Conference to reach consensus in August, the next review cycle will start by looking at strengthening the process. Iran’s nuclear capabilities remain a concern, and North Korea’s nuclear weapons programme is a growing threat. So, we are left with a question: will 2023 be the year of  nuclear conflict or the year when states get busy again on non-proliferation and disarmament?  

Africa’s mounting debt

Joseph Asunka, Chief Executive Officer, Afrobarometer

Inflation is at historic highs in several African economies. Meanwhile, many African countries including Nigeria, Zimbabwe and Democratic Republic of Congo will hold  elections in 2023, driving up public spending, increasing inflationary pressures and exacerbating poverty. According to Afrobarometer data, the proportion of Africans experiencing high levels of poverty has increased from 19 per cent in 2014/2015 to  26 per cent in 2021/2022.

Worse still, many of those countries holding elections are either, like Zimbabwe, in debt distress – that is unable to honour their obligations to creditors – or at high risk of debt distress, like Nigeria. This makes the elections in Zimbabwe and Nigeria critical. The expiration of the World Bank/IMF-backed debt service suspension initiative in 2021 has only amplified this risk. What are viable policy options to tackle this dire economic predicament? A debt service moratorium, debt cancellation and serious attention to fiscal discipline.

Feminist foreign policy

Daniela Philipson García, Co-founder of Internacional Feminista, and a PhD candidate, Monash University

Feminist Foreign Policy (FFP) is under threat. The war in Ukraine led to strengthened military budgets and alliances at odds with FFP’s human security and peace-centred approaches. Sweden’s new right-wing government reversed its FFP. In Mexico, the first Global South country to adopt an FFP, Congress has voted to expand the military’s role to curb cartel-related violence, in contradiction of its FFP. The second anniversary of the US withdrawal from Afghanistan will be a moment to assess how foreign policy, diplomacy and women’s and girls’ rights have been affected globally. 

There is hope. Germany, whose coalition government adopted an FFP in 2021, is to publish more guidelines in the spring. The governments of Colombia and Chile have announced their own FFPs. Colombia’s first National Action Plan on Women, Peace and Security, to be announced at the UN General Assembly in September, is expected to set a standard for a region submerged in violence. 

After percolating for roughly a year, NSF has issued the next solicitation for the National Quantum Virtual Lab program — this one focused on design and implementation phases of the […]

The post NSF Issues Next Solicitation and More Detail on National Quantum Virtual Laboratory appeared first on HPCwire.

After much anticipation, the National Institute of Standards and Technology (NIST) issued its first Post Quantum Cryptography (PQC) standards today. They are intended to defeat efforts by quantum computers powerful […]

The post NIST Issues Post Quantum Cryptography Standards and Calls for their Adoption appeared first on HPCwire.

WASHINGTON, Oct. 30, 2024 — The U.S. Department of the Treasury (Treasury) today issued a final rule (Final Rule) to implement Executive Order 14105 of August 9, 2023, “Addressing United […]

The post US Treasury Issues Final Rule Addressing Investments in Certain National Security Technologies and Products appeared first on HPCwire.

SAN JOSE, Calif., Nov. 6, 2024 — Super Micro Computer, Inc. (Nasdaq: SMCI), a Total IT Solution Provider for AI, Cloud, Storage, and 5G/Edge, has provided an update from the independent […]

The post Supermicro Releases Preliminary Q1 Earnings Amid Ongoing Compliance Issues appeared first on HPCwire.

Last week the University of Colorado (Boulder), the CUbit Quantum Initiative, and the Elevate Quantum consortium released workforce roadmap for educating and building a quantum workforce. “This roadmap provides a […]

The post Go (Mountain) West, Quantum Workers! CU, CUbit, and Elevate Quantum Issue Workforce Roadmap appeared first on HPCwire.

Intersect360 Research has released a comprehensive new report concerning the challenges facing the combined fields of high-performance computing (HPC) and artificial intelligence (AI). Titled “Issues Facing the HPC-AI Industry: Insights […]

The post Report from HALO Details Issues Facing HPC-AI Industry appeared first on HPCwire.

A team of U.S. employees at Hachette wrote an open letter to management in protest over a new conservative book imprint created in wake of last week's Donald Trump victory headed by a known far-right publisher.

This year's November elections—a preview to next year's nationwide showdowns—cast their own spotlight on education, a dynamic that played out most prominently in the Kentucky governor's race, where teachers organized to unseat a combative incumbent who'd sparred with them.

Concerns about local school systems can pose recruitment and retention hurdles for the armed services as they seek to meet the needs of military families.

Seek Academy in Newark, N.J., has added a social justice class for students in kindergarten through 4th grades to help them make sense of some of the most controversial issues of the day, including the "take the knee" debate.

As lawmakers weigh expansion of the state’s voucher and tax-credit scholarship programs, some renew a push for anti-discrimination protection for lesbian, gay, bisexual, transgender, and queer students.

This year's November elections—a preview to next year's nationwide showdowns—cast their own spotlight on education, a dynamic that played out most prominently in the Kentucky governor's race, where teachers organized to unseat a combative incumbent who'd sparred with them.

Tessa E.S. Charlesworth
Sep 11, 2019; 39:7228-7243
Viewpoints

Over 100 professional vacancies are in the process of being released and opened for applications. They cover mainly technical areas of work in headquarters and regional offices.

In addition, global calls [...]

This edition of The State of Agricultural Commodity Markets (SOCO) discusses how trade policies, based on both multilateral and regional approaches, can address today’s challenges for sustainable development. 

This year’s report should dispel any lingering doubts that the world is moving backwards in its efforts to end hunger, food insecurity and malnutrition in all its forms. We are [...]

Your feedback on the First Continental Congress, Douglas MacArthur and England's tangled history

Atlantic staff writer Frank Foer interviews Damion Thomas about athletes moving from a position of apathy to engagement

A new study identified the tiny pollutants in the olfactory bulbs of eight cadavers, suggesting microplastics can travel through the nose to the brain

On this day in 1690, "Publick Occurrences Both Forreign and Domestick" attracted colonial officials' ire by repeating a scandalous rumor and condemning a British alliance with the Mohawk

Scientists sent bioengineered heart tissue samples to the ISS to study how to keep astronauts safe during future long-term space travel

The president atoned for the federal government's role in forcing Native American children into boarding schools, where many were abused and more than 900 died

As Week 3 of the provincial election campaign begins, there are questions about how Nova Scotia's major political parties plan to combat the rising number of opioid overdose deaths. 

The Société de transport de Montréal (STM) has established a non-urgent text line for transit users to signal security issues in the Metro network.

We've heard what the candidates want to do about community safety in Saskatoon. Here's what the people already doing the work say the new mayor and council should do after the civic election.

Officials have issued wind and rainfall warnings for Tuesday night in several regions as another fall storm approaches southwestern B.C.

SOLIDWORKS Corporation joins effort, pledging financial support for FIRST Robotics mentorship program

The College Board's national experiment with virtual AP exams gets underway this week amid accusations and stern warnings about student cheating.

In the world’s wealthiest country, why is broadband access denied to so many and in such high numbers? Mark Lieberman investigates.

The vice presidential candidate was bused to school as child. Her experience could inform national education policy, writes Jonathan E. Collins.

With the stakes high in November, school shutdowns, reopenings, and money for recovery could put education front and center for voters, and complicate things for politicians and activists alike.

The vice presidential candidate was bused to school as child. Her experience could inform national education policy, writes Jonathan E. Collins.

So many years after vouchers began, we still can't agree on their benefits.